Azabicyclic-substituted fused heteroaryl compounds for the treatment of disease

ABSTRACT

The invention provides compounds of Formula I:  
                 
 
wherein Azabicyclo is  
                 
These compounds may be in the form of pharmaceutical salts or compositions, racemic mixtures, or pure enantiomers thereof. The compounds of Formula I are useful in pharmaceuticals in which α7 is known to be involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application Ser.No. 60/326,629 and U.S. provisional application Ser. No. 60/326,565 bothfiled on 02 Oct. 2001, under 35 USC 119(e)(i), U.S. provisionalapplication Ser. No. 60/334,886 filed on 15 Nov. 2001, under 35 USC119(e)(i), and U.S. provisional application Ser. No. 60/339,633 filed on12 Dec. 2001, under 35 USC 119(e)(i), which are incorporated herein byreference in their entirety.

FIELD OF INVENTION

Nicotinic acetylcholine receptors (nAChRs) play a large role in centralnervous system (CNS) activity. Particularly, they are known to beinvolved in cognition, learning, mood, emotion, and neuroprotection.There are several types of nicotinic acetylcholine receptors, and eachone appears to have a different role in regulating CNS function.Nicotine affects all such receptors, and has a variety of activities.Unfortunately, not all of the activities are desirable. In fact, one ofthe least desirable properties of nicotine is its addictive nature andthe low ratio between efficacy and safety. The present invention relatesto molecules that have a greater effect upon the α7 nAChRs as comparedto other closely related members of this large ligand-gated receptorfamily. Thus, the invention provides compounds that are active drugmolecules with fewer side effects.

BACKGROUND OF THE lNVENTION

Cell surface receptors are, in general, excellent and validated drugtargets. nAChRs comprise a large family of ligand-gated ion channelsthat control neuronal activity and brain function. These receptors havea pentameric structure. In mammals, this gene family is composed of ninealpha and four beta subunits that co-assemble to form multiple subtypesof receptors that have a distinctive pharmacology. Acetylcholine is theendogenous regulator of all of the subtypes, while nicotinenon-selectively activates all nAChRs.

The α7 nAChR is one receptor system that has proved to be a difficulttarget for testing. Native α7 nAChR is not routinely able to be stablyexpressed in most mammalian cell lines (Cooper and Millar, J.Neurochem., 1997, 68(5):2140-51). Another feature that makes functionalassays of α7 nAChR challenging is that the receptor is rapidly (100milliseconds) inactivated. This rapid inactivation greatly limits thefunctional assays that can be used to measure channel activity.

Recently, Eisele et al. has indicated that a chimeric receptor formedbetween the N-terminal ligand binding domain of the α7 nAChR (Eisele etal., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminaldomain of the 5-HT₃ receptor expressed well in Xenopus oocytes whileretaining nicotinic agonist sensitivity. Eisele et al. used theN-terminus of the avian (chick) form of the α7 nAChR receptor and theC-terminus of the mouse form of the 5-HT₃ gene. However, underphysiological conditions the α7 nAChR is a calcium channel while the5-HT₃R is a sodium and potassium channel. Indeed, Eisele et al. teachesthat the chicken α7 nAChR/ mouse 5-HT₃R behaves quite differently thanthe native α7 nAChR with the pore element not conducting calcium butactually being blocked by calcium ions. WO 00/73431 A2 reports on assayconditions under which the 5-HT₃R can be made to conduct calcium. Thisassay may be used to screen for agonist activity at this receptor.

U.S. Pat. No. 6,054,464 discloses azabicyclic esters of carbamic acidsuseful in therapy, especially in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, as well asintermediates and use of intermediates in synthesis.

U.S. Pat. No. 5,977,144 discloses compositions for benzylidene- andcinnamylidene-anabaseines and methods for using these compositions fortreating conditions associated with defects or malfunctioning ofnicotinic subtypes brain receptors. These compositions target the α7receptor subtype with little or no activation of the α4β2 or otherreceptor subtypes.

U.S. Pat. No. 5,599,937 discloses heteroaromatic quinuclidines used fortreating diseases related to muscarinic receptor function.

U.S. Pat. No. 5,561,149 discloses the use of a mono or bicycliccarbocyclic, or heterocyclic carboxylic acid, ester or amide or animidazolyl carbazol in the manufacture of a medicament suitable for thetreatment of stress-related psychiatric disorders, for increasingvigilance, for the treatment of rhinitis or serotonin-induced disordersand/or coadministration with another active agent to increase thebioavailability thereof, or for nasal administration.

U.S. Pat. No. 5,543,426 discloses the use of certain 3,7-disubstitutedindole compounds for treating depression or cognitive disorders.

U.S. Pat. No. 5,434,161 discloses imidazopyridines as serotonergic 5-HT₃antagonists.

U.S. Pat. No. 5,362,740 discloses dihydrobenzofuran carboxamides usefulin treating CNS disorders, but motility disorders, and/or emisis and/orpain in mammals, and/or migraine.

U.S. Pat. No. 5,352,685 discloses thieno[3,2-b]pyridine derivativeseffective for the prevention and therapeutical treatment of the symptomscaused by gastric hypanakinesis, such as heartburn, abdominal distensionfeeling, anorexia, unpleasant feeling on upper abdomen, abdominalgia,nausea, vomiting, etc. caused by the underlying diseases such as acuteand chronic gastritis, stomach and duodenum ulcer, gastroneurosis,gastroptosis, etc.

U.S. Pat. No. 5,342,845 discloses indole derivatives and drugs. Thecompound of the invention is disclosed as being effective as agastrointestinal motor activity regulator, antimigraine, antipsychoticor antianxiety drug and for dementia or orthostatic hypotension.

U.S. Pat. No. 5,322,951 discloses certain 1-(2,3-dihydro-indole)carbonylintermediates useful for preparing 1-(2,3-dihydro)-1-carboxamide finalproducts that possess 5-HT M-receptor antagonist activity.

U.S. Pat. No. 5,272,154 discloses 3,7 substituted indole and indazolecompounds and pharmaceutical compositions containing them and aredisclosed as being useful for the treatment of psychiatric disorders.

U.S. Pat. No. 5,217,975 discloses azabicyclic compounds for treatingdementia.

U.S. Pat. No. 5,039,680 discloses 5-HT₃ antagonists in preventing orreducing dependency on dependency-inducing agents.

U.S. Pat. No. 5,001,133 discloses substituted benzoic acid heterocyclicamides and esters as being serotonin M antagonists.

U.S. Pat. No. 4,985,437 discloses the use of certain compounds which actas antagonists of 5-hydroxytryptamine (5-HT) at 5-HT₃ receptors for thetreatment of cognitive disorders such as attentional and memory deficitsand dementia states.

U.S. Pat. No. 4,983,600 discloses heterocyclic compounds useful as 5-HT₃antagonists.

U.S. Pat. No. 4,973,594 discloses the use of compounds which act asantagonists of 5-hydroxytryptamine (5-HT) at 5-HT₃ receptors for thetreatment of depression.

U.S. Pat. No. 4,937,247 discloses 1-acyl indazoles that are disclosed ashaving 5-HT₃ antagonist activity.

U.S. Pat. No. 4,935,511 discloses benzoxazine and benzoxazepincarboxamide 5-HT₃ antagonists properties including CNS, anti-emetic andgastric prokinetic activity and which are void of any significant D₂receptor binding affinity.

U.S. Pat. No. 4,921,982 discloses5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which areuseful as intermediates for 5-HT₃ antagonists.

U.S. Pat. No. 4,920,219 discloses substituted saturated and unsaturatedindole quinoline and benzazepine carboxamides and their valuable use as5-HT₃ antagonists having CNS and gastric prokinetic activity void of anysignificant D₂ receptor binding properties.

U.S. Pat. No. 4,920,127 discloses substituted indoles and their use as5-HT₃ receptor antagonists.

U.S. Pat. No. 4,910,193 discloses treatment of gastrointestinaldisorders.

U.S. Pat. No. 4,888,353 discloses carboxamides useful as antiemetic orantipsychotic agents.

U.S. Pat. No. 4,882,327 discloses certain heterocyclic N-substitutedcarboxamides having 5-HT₃ receptor antagonist activity.

U.S. Pat. No. 4,845,092 discloses a method of treatment of visceral painin mammals, including humans.

U.S. Pat. No. 4,835,162 discloses agonists and antagonists to nicotineas smoking deterrents.

U.S. Pat. No. 4,822,795 discloses pharmaceutically useful esters andamides.

U.S. Pat. No. 4,803,199 discloses pharmaceutically useful heterocyclicacid esters and amides or alkylene bridged peperidines as serotonin Mantagonists.

U.S. Pat. No. 4,798,829 discloses 1-azabicyclo[3.2.2]nonane derivativeshaving gastric motility enhancing activity and/or anti-emetic activityand/or 5-HT receptor antagonist activity.

U.S. Pat. No. 4,797,406 discloses amides and esters containing bridgedpiperidines and use as serotonin M antagonists.

U.S. Pat. No. 4,721,720 discloses a method of treating emesis, anxietyand/or irritable bowl syndrome.

U.S. Pat. No. 4,612,319 discloses bridged quinolizinidinylamides,compositions containing them and methods for their use.

U.S. Pat. No. 4,605,652 discloses a method of enhancing memory orcorrecting memory deficiency with arylamido (andarylthioamido)-azabicycloalkanes, and the pharmaceutically acceptableacid addition salts, hydrates and alcoholates thereof.

WO 01/60821 A1 discloses novel biarylcarboxamides and their use intherapy, especially in the treatement of prophylaxis of psychotic andintellectual impairment conditions.

WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives and use intherapy, especially in the treatment of prophylaxis of psychoticdisorders and intellectual impairment disorders.

WO 00/73431 A2 discloses two binding assays to directly measure theaffinity and selectivity of compounds at the α7 nAChR and the 5-HT₃R.The combined use of these functional and binding assays may be used toidentify compounds that are selective agonists of the α7 nAChR.

WO 99/20633 discloses benzoazine derivatives having an antagonistactivity for 5-HT₃/5-HT₄ receptors.

WO 97/35860 discloses novel benzimidazol derivatives having an affinityfor the serotoninergic 5-HT₃/5-HT₄ receptors.

WO 96/33186 discloses substituted dihydrobenzofuran derivatives as 5-HT₄agonists.

WO 95/27490 discloses serotonin antagonists (5-HT₃) for treatingfibromyalgia.

WO 95/04742 discloses tropyl 7-azaindol-3-ylcarboxyamides as antitussiveagents.

WO 92/10494 discloses novel compounds that are 5-HT₃ receptorantagonists.

WO 91/17161 discloses isoquinoline amides and esters as 5-HT₃ receptorantagonists.

WO 91/09593 discloses 5-HT₃ antagonists for treatment of nausea,bradycardia or hypotension associated myocardial instability.

WO 90/14347 A as abstracted in chemical abstract 1991:143,158 disclosesN-quinuclidinyl-indolecarboxamide derivatives as being antiemetics.

EP 512 350 A2 discloses 3-(indolyl-2-carboxamido) quinuclidines usefulfor treating diseases characterized by an excess or enhanced sensitivityto serotonin, e.g., psychosis, nausea, vomiting, dementia or othercognitive diseases, migraine, diabetes. The compound may be used tocontrol anxiety, aggression, depression, and pain. The compounds aredisclosed as serotonin 5-HT₃ antagonists.

EP 496 064 A1 discloses a process for the preparation of substitutedbenzofuran derivatives. The compounds are disclosed as being useful5-HT₃ receptor antagonists.

EP 483 836 A1 discloses pyrazolo[1,5-a]pyridine-3-carboxylic acidderivatives, their preparation process, and serotonin receptorantagonists containing them as active ingredients.

DE 3810552 A1 discloses esters and amides of indolyl-,benzo[b]thiophenyl-,benzo[b]furancarboxylic acids or 4-amino-2methoxy-benzoic acids with N-heterocyclic or N-heterobicyclic alcoholsor amines. The compounds disclosed have activity against pain especiallymigraine, as an anti-arrhythmic for gastrointestinal disturbances,stomach disturbances, gastritis ulcer, gall bladder, spastic colon,Crohn's disease, ulcerative colitis, carcinoid syndrome, diarrhea ofvarious types. The compounds are also disclosed as speeding stomachemptying, controlling gastro duodenal and gastro esophageal reflux,disturbances of esophageal motility, hiatal hernia, cardiacinsufficiency, hypotonic stomach, paralytic ileus, manic depressivepsychosis and other psychoses. The compounds are also disclosed asuseful for stress related diseases, senility, and enhancement of nasalabsorption of other agents, e.g., in the treatment of emesis.

In Bioorg. & Med. Chem. Lett. 11 (2001) 319-321, the 5-HT₃ antagonisttropisetron (ICS 205-930) is discussed as a potent and selective α7nicotinic receptor partial agonist.

In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that thebrain α7 nicotinic receptor may be an important therapeutic target forthe treatment of Alzheimer's disease using DMXBA which is known asGTS-21.

In Bioorg. & Med. Chem. Lett. 9 (1999) 1895-1900, it is discussed thediscovery of a highly potent, functionally-selective muscarinic M₁agonist.

In Bioorg. & Med. Chem. Lett. 4 (1994) 695-698, it is discussedpyrazolo[1,5-a]pyridines and pyrazolo[1,5-b]pyridazines as 5-HT₃antagonists.

In Eur. J. Med. Chem., 34 (1999) 415-422, benzimidazole-2-carboxylicacid amides and esters are discussed as a new structural class of 5-HT₃ligands.

SUMMARY OF THE INVENTION

The present invention discloses compounds of the Formula I:

wherein Azabicyclo is

provided that the bond between the —C(═X)— group and the W group may beattached at any available carbon atom within the W group as provided inR₃, R₆, and R₁₅;

-   -   X is O, or S;    -   R₀ is H, lower alkyl, substituted lower alkyl, or halogenated        lower alkyl;    -   Each R₁ is H, alkyl, cycloalkyl, halogenated alkyl, substituted        phenyl, or substituted naphthyl;    -   Each R₂ is alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, aryl, F, Cl, Br, I, or R₂ is absent provided that        k₂, k₅, or k₆ is 0;    -   R₂₋₃ is H, alkyl, substituted alkyl, halogenated alkyl, F, Cl,        Br, or I;    -   k₂ is 0 or 1;    -   k₅ and k₆ are independently 0, 1, or 2;    -   A---A′---A″ is N(R₄)—C(R₃)═C(R₃), N═C(R₃)—C(R₁₅)₂,        C(R₃)═C(R₃)—N(R₄), C(R₃)₂—N(R₄)—C(R₃)₂, C(R₁₅)₂—C(R₃)═N,        N(R₄)—C(R₃)₂—C(R₃)₂, C(R₃)₂—C(R₃)₂—N(R₄), O—C(R₃)═C(R₃),        O—C(R₃)₂—C(R₃)₂, C(R₃)₂—O—C(R₃)₂, C(R₃)═C(R₃)—O,        C(R₃)₂—C(R₃)₂—O, S—C(R₃)═C(R₃), S—C(R₃)₂—C(R₃)₂,        C(R₃)₂—S—C(R₃)₂, C(R₃)═C(R₃)—S, or C(R₃)₂—C(R₃)₂—S;    -   Each R₃ is independently a bond to the core molecule provided        that only one R₃ and no R₆ or R₁₅ is also said bond, H, alkyl,        substituted alkyl, halogenated alkyl, alkenyl, substituted        alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl,        halogenated alkynyl, —CN, —NO₂, F, Br, Cl, I, —OR₁₉,        —C(O)N(R₀)₂, —N(R₁₀)₂, —SR₁₉, —S(O)₂R₁₉, —C(O)R₁₉, —CO₂R₁₉,        aryl, R₇, or R₉;    -   J, L, M, and Q are N or C(R₆) provided that only one of J, L, M,        or Q, is N and the others are C(R₆), further provided that when        the core molecule is attached to the pyridinyl moiety at M, Q is        C(H), and further provided that there is only one attachment to        the core molecule;    -   G and Y are C(R₆), provided that when the molecule is attached        to the phenyl moiety at Y, G is CH;    -   R₄ is H, alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,        heterocycloalkyl, halogenated heterocycloalkyl, substituted        heterocycloalkyl, R₇, or R₉;    -   Each R₅ is independently H, lower alkyl, or lower alkenyl;    -   Each R₆ is independently H, F, Br, I, Cl, —CN, —CF₃, —OR₅, —SR₅,        —N(R₅)₂, or a bond to the core molecule provided that only one        R₆ and no R₃ or R₁₅ is said bond;    -   V is selected from O, S, or N(R₄);    -   R₇ is 5-membered heteroaromatic mono-cyclic moieties containing        within the ring 1-3 heteroatoms independently selected from the        group consisting of ═N—, —N(R₁₇)—, —O—, and —S—, and having 0-1        substituent selected from R₁₈ and further having 0-3        substituents independently selected from F, Cl, Br, or I, or R₇        is 9-membered fused-ring moieties having a 6-membered ring fused        to a 5-membered ring including the formula    -    wherein G₁ is O, S or NR₁₇,    -    wherein G is C(R₁₆) or N, and each G₂ and G₃ are independently        selected from C(R₁₆)₂—C(R₁₆), O, S, N, and N(R₈), provided that        both G₂ and G₃ are not simultaneously O, simultaneously S, or        simultaneously O and S, or    -    wherein G is C(R₁₆) or N, and each G₂ and G₃ are independently        selected from C(R₁₆)₂, C(R₁₆), O, S, N, and N(R₁₇), each        9-membered fused-ring moiety having 0-1 substituent selected        from R₁₈ and further having 0-3 substituent(s) independently        selected from F, Cl, Br, or I, wherein the R₇ moiety attaches to        other substituents as defined in formula I at any position on        either ring as valency allows;    -   Each R₈ is independently H, alkyl, halogenated alkyl,        substituted alkyl, cycloalkyl, halogenated cycloalkyl,        substituted cycloalkyl, heterocycloalkyl, halogenated        heterocycloalkyl, substituted heterocycloalkyl, R₇, R₉, phenyl,        or substituted phenyl;

R₉ is 6-membered heteroaromatic mono-cyclic moieties containing withinthe ring 1-3 heteroatoms selected from ═N— and having 0-1 substituentselected from R₁₈ and 0-3 substituent(s) independently selected from F,Cl, Br, or I, or R₉ is 10-membered heteroaromatic bi-cyclic moietiescontaining within one or both rings 1-3 heteroatoms selected from ═N—,including, but not limited to, quinolinyl or isoquinolinyl, each10-membered fused-ring moiety having 0-1 substituent selected from R₁₈and 0-3 substituent(s) independently selected from F, Cl, Br, or I, andhaving a bond directly or indirectly attached to the core molecule wherevalency allows;

-   -   Each R₁₀ is independently H, alkyl, cycloalkyl,        heterocycloalkyl, alkyl substituted with 1 substituent selected        from R₁₃, cycloalkyl substituted with 1 substituent selected        from R₁₃, heterocycloalkyl substituted with 1 substituent        selected from R₁₃, halogenated alkyl, halogenated cycloalkyl,        halogenated heterocycloalkyl, phenyl, or substituted phenyl;    -   Each R₁₁ is independently H, alkyl, cycloalkyl,        heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or        halogenated heterocycloalkyl;

R₁₂ is —NO₂, —CN, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁,—SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or—NR₁₁S(O)₂R₁₁;

-   -   R₁₃ is —CN, —CF₃, —NO₂, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁,        —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁;    -   Each R₁₄ is H, alkyl, substituted alkyl, halogenated alkyl,        alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl,        substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, —CN,        —NO₂, —OR₁₉, —C(O)N(R₁₀)₂, —N(R₁₀)₂, —SR₁₉, —S(O)₂R₁₉, —C(O)R₁₉,        —CO₂R₁₉, aryl, R₇ or R₉;    -   Each R₁₅ is independently alkyl, substituted alkyl, halogenated        alkyl, alkenyl, substituted alkenyl, halogenated alkenyl,        alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I,        —CN, —NO₂, —OR₁₉, —C(O)N(R₁₀)₂, —N(R₁₀)₂, —SR₁₉, —CO₂R₁₉, aryl,        R₇, R₉, or a bond to the core molecule provided that only one        R₁₅ and no R₆ or R₃ is said bond;    -   Each R₁₆ is independently H, alkyl, cycloalkyl,        heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,        halogenated heterocycloalkyl, substituted alkyl, substituted        cycloalkyl, substituted heterocycloalkyl, F, Cl, Br, I, —NO₂,        —CN, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁,        —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, or a bond directly        or indirectly attached to the core molecule, provided that there        is only one said bond to the core molecule within the 9-membered        fused-ring moiety, further provided that the fused-ring moiety        has 0-1 substituent selected from alkyl, cycloalkyl,        heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,        halogenated heterocycloalkyl, substituted alkyl, substituted        cycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁,        —NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,        —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁, and further provided that the        fused-ring moiety has 0-3 substituent(s) selected from F, Cl,        Br, or I;    -   R₁₇ is H, alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,        phenyl, —SO₂R₈, or phenyl having 1 substituent selected from R₁₈        and further having 0-3 substituents independently selected from        F, Cl, Br, or I;    -   R₁₈ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,        halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁₁,        —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,        —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, —NO₂, alkyl substituted with 1-4        substituent(s) independently selected from F, Cl, Br, I, or R₁₃,        cycloalkyl substituted with 1-4 substituent(s) independently        selected from F, Cl, Br, I, or R₁₃, or heterocycloalkyl        substituted with 1-4 substituent(s) independently selected from        F, Cl, Br, I, or R₁₃;    -   R₁₉ is H, alkyl, cycloalkyl, substituted alkyl, halogenated        alkyl, substituted phenyl, or substituted naphthyl;    -   or pharmaceutical composition, pharmaceutically acceptable salt,        racemic mixture, or pure enantiomer thereof.

The compound of Formula I are used to treat a disease or condition,wherein the diseases, disorders, and/or condition is any one or more orcombination of the following: cognitive and attention deficit symptomsof Alzheimer's, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, tardive dyskinesia,Pick's disease, dysregulation of food intake including bulemia andanorexia nervosa, withdrawal symptoms associated with smoking cessationand dependant drug cessation, Gilles de la Tourette's Syndrome,age-related macular degeneration, glaucoma, neurodegeneration associatedwith glaucoma, or symptoms associated with pain.

Embodiments of the invention may include one or more or combination ofthe following.

The compound of Formula I, wherein X is O.

The compound of Formula I, where X is S.

The compound of Formula I, where Azabicyclo is any one or more of I, II,III, IV, V, or VI.

The compound of Formula I, where W is any one or more of (a), (b), or(c).

The compound of Formula I, where W is any one or more of the following:

-   thieno[2,3-b]pyridin-2-yl, thieno[2,3-b]pyridin-5-yl,    thieno[2,3-b]pyridin-6-yl, thieno[3,2-b]pyridin-2-yl,    thieno[3,2-b]pyridin-5-yl, thieno[3 ,2-b]pyridin-6-yl,    thieno[2,3-c]pyridin-2-yl, thieno[2,3-c]pyridin-5-yl,    thieno[3,2-c]pyridin-2-yl, thieno[3,2-c]pyridin-6-yl,    furo[3,2-c]pyridin-2-yl, furo[3,2-c]pyridin-6-yl,    furo[2,3-b]pyridin-2-yl, furo[2,3-c]pyridin-2-yl,    furo[2,3-c]pyridin-5-yl, 2,3-dihydrofuro[2,3-c]pyridin-5-yl,    1H-pyrrolo[2,3-c]pyridin-5-yl, thieno[3,4-c]pyridin-6-yl,    benzothieno[3,2-c]pyridine-3-yl, benzothieno[2,3-c]pyridin-3-yl,    benzofuro[3,2-c]pyridin-3-yl, or benzofuro[2,3-c]pyridin-3-yl,    -   any of which is optionally substituted on up to 4 different        carbon atoms as valency allows and as allowed by the definition        of W with F, Br, Cl, I, —CN, —NO₂, —CF₃, —OR₅, —OR₁₉, —SR₅,        —SR₁₉, —N(R₅)₂, —N(R₁₀)₂, —C(O)R₁₉, —CO₂R₁₉, —C(O)N(R₁₀)₂,        —S(O)₂R₁₉, alkyl, substituted alkyl, halogenated alkyl, alkenyl,        substituted alkenyl, halogenated alkenyl, alkynyl, substituted        alkynyl, halogenated alkynyl, aryl, R₇, R₉,    -   and further where any of which is optionally substituted on a        nitrogen as allowed by the definition of W with alkyl,        halogenated alkyl, substituted alkyl, cycloalkyl, halogenated        cycloalkyl, substituted cycloalkyl, heterocycloalkyl,        halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇,        or R₉,    -   provided that one carbon is used to bond W to the core molecule.        One of ordinary skill in the art will recognize what        substitution is allowed by comparing the named moieties with the        allowed moieties for W.

The compound of Formula I, where (a), (b), or (c) is optionallysubstituted as the definition of W allows with up to four substituentsbeing F, Br, Cl, I, —CN, —CF₃, —OR₅, —SR₅, —N(R₅)₂, —C(O)R₅, —CO₂R₅,—C(O)N(R₁₀)₂, —S(O)₂R₅, lower alkyl, lower substituted alkyl, or loweralkynyl,

-   -   where R₁₀ is H, lower halogenated alkyl, or lower alkyl        optionally substituted with —CN, —CF₃, —NO₂, —OR₁₁, —SR₁₁,        —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁,        or —NR₁₁S(O)₂R₁₁, where R₁₁ is H, lower alkyl, lower halogenated        alkyl, lower substituted alkyl. One of ordinary skill in the art        will recognize that where —OR₁₉, —SR₁₉, —C(O)R₁₉, or —CO₂R₁₉ is        an allowed substituent, —OR₅, —SR₅, —C(O)R₅, or —CO₂R₅ is also        allowed due to the groups within R₅ being a subgroup of what is        in R₁₉. Furthermore, one of ordinary skill in the art can        identify which substituents are allowed on carbon or nitrogen as        allowed by the definition of W.

Lower alkynyl is straight- and branched-chained moieties having from 2-4carbon atoms and having at least one carbon-carbon triple bond.

Another group of compounds of Formula I include compounds where R₁ is H,alkyl, or cycloalkyl.

Another group of compounds of Formula I include compounds whereAzabicyclo is II, V, or VI and where each k₂, k₅, and k₆ isindependently 0 or 1. Another group of compounds of Formula I includecompounds where R₂ is alkyl, halogenated alkyl, substituted alkyl, or isabsent provided that k₂, k₅, or k₆ is 0. Another group of compounds ofFormula I include compounds where R₁ is H or lower alkyl, and wherein R₂is lower alkyl or is absent provided that k₂, k₅, or k₆ is 0.

Another group of compounds of Formula I include compounds whereAzabicyclo is I and where R₂ is alkyl, halogenated alkyl, or substitutedalkyl, or where Azabicyclo is III or IV and where R₂₋₃ is H, alkyl, orsubstituted alkyl.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   Exo-4(R)—N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   Exo-N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   (+)-N-[endo-1-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamide;-   (−)-N-[endo-1-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-[(exo)-azabicyclo[2.2.1]hept-3-yl]furo[3,2-c]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.1]-hept-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;-   Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;-   (exo)-N-[1-Azabicyclo[3.2.1]oct-3-yl]-3-methylfuro[2,3-c]pyridine-5-carboxamide;-   (3R,5R)—N-[1-azabicyclo[3.2.1]oct-3-yl]-3-methylfuro[2,3-c]pyridine-5-carboxamide;-   Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-furo[2,3-b]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-furo[2,3-b]pyridine-2-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-furo[2,3-b]pyridine-2-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-furo[2,3-b]pyridine-2-carboxamide;-   Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-3-isopropyl    furo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-2-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-b]pyridine-2-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-b]pyridine-2-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-b]pyridine-5-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-b]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-2-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-c]pyridine-2-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-c]pyridine-2-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-2-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-b]pyridine-2-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-b]pyridine-2-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-b]pyridine-5-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-b]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-2-carboxamide;-   Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-c]pyridine-5-carboxamide;-   Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-c]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-c]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(1-azabicyclo[2.2.1]hept-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide;    or-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide.

For all compounds identified, the naming of a specific enantiomer doesnot limit the scope of the invention, but is for exemplification. Thenaming of a specific enantiomer includes racemic mixtures of thatcompound. For example, namingexo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamideincludes within the scope of the present inventionexo-(rac)-N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide.When a pure enantiomer is discussed, the compound is a racemic mixtureor the pure enantiomer pure thereof. When Azabicyclo is II, pureenantiomers include exo-4(S) 1-azabicyclo[2.2.1]hept-3-yl. WhenAzabicyclo is V, pure enantiomers include exo-3(R), 5(R)1-azabicyclo[3.2.1]oct-3-yl.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-vinylfuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(3-hydroxyprop-1-ynyl)furo[3,2-c]pyridine-6-carboxamide;-   methyl    3-(6-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylamino]carbonyl}furo[3,2-c]pyridin-2-yl)prop-2-ynoate;-   2-(3-amino-3-oxoprop-1-ynyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]furo[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyanofuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-chlorofuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-fluorofuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-iodofuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(methylthio)furo[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(methylamino)furo[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(formylamino)furo[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-[formyl(methyl)amino]furo[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-[(trifluoroacetyl)amino]furo[3,2-c]pyridine-6-carboxamide;-   N-6-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]furo[3,2-c]pyridine-2,6-dicarboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formylfuro[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(trifluoroacetyl)furo[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(methylsulfonyl)furo[3,2-c]pyridine-6-carboxamide;-   methyl    6-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylamino]carbonyl}furo[3,2-c]pyridine-2-carboxylate;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-vinylthieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-ethynylthieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-prop-1-ynylthieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(3-hydroxyprop-1-ynyl)thieno[3,2-c]pyridine-6-carboxamide;-   methyl    3-(6-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylaming]carbonyl}thieno[3,2-c]pyridin-2-yl)prop-2-ynoate;-   2-(3-amino-3-oxoprop-1-ynyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyanothieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-chlorothieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-fluorothieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-iodothieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-trifluoromethylthieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(methylthio)thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(methylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(formylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-[formyl(methyl)amino]thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]    -2-[(trifluoroacetyl)amino]thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(cyclopropylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-[dimethylamino]thieno[3,2-c]pyridine-6-carboxamide;-   N-6-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]thieno[3,2-c]pyridine-2,6-dicarboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formylthieno[3,2-c]pyridine-6-carboxamide;-   2-acetyl-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(trifluoroacetyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(methylsulfonyl)thieno[3,2-c]pyridine-6-carboxamide;-   methyl    6-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylamino]carbonyl}thieno[3,2-c]pyridine-2-carboxylate-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-vinylfuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(3-hydroxyprop-1-ynyl)furo[2,3-c]pyridine-5-carboxamide;-   methyl    3-(5-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylamino]carbonyl}furo[2,3-c]pyridin-3-yl)prop-2-ynoate;-   3-(3-amino-3-oxoprop-1-ynyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyanofuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-fluorofuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-iodofuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(methylthio)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(methylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(formylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-[formyl(methyl)amino]furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-[(trifluoroacetyl)amino]furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(cyclopropylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;-   N-5-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-3,5-dicarboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-formylfuro[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(trifluoroacetyl)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(methylsulfonyl)furo[2,3-c]pyridine-5-carboxamide;-   methyl    5-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylamino]carbonyl}furo[2,3-c]pyridine-3-carboxylate;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-vinylthieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynylthieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynylthieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(3-hydroxyprop-1-ynyl)thieno[2,3-c]pyridine-5-carboxamide;-   methyl    3-(5-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylamino]carbonyl}thieno[2,3-c]pyridin-3-yl)prop-2-ynoate;-   3-(3-amino-3-oxoprop-1-ynyl)-N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyanothieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chlorothieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-fluorothieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-iodothieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-trifluoromethylthieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(methylthio)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(methylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(formylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-[formyl(methyl)amino]thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-[(trifluoroacetyl)amino]thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(cyclopropylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-[dimethylamino]thieno[2,3-c]pyridine-5-carboxamide;-   N-5-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]thieno[2,3-c]pyridine-3,5-dicarboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-formylthieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(trifluoroacetyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(methylsulfonyl)thieno[2,3-c]pyridine-5-carboxamide;-   methyl    5-{[exo-4(S)-1-azabicyclo[2.2.1]hept-3-ylamino]carbonyl}thieno[2,3-c]pyridine-3-carboxylate;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(phenylethynyl)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(3,3,3-trifluoroprop-1-ynyl)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(3,3-difluoroprop-1-ynyl)furo[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(phenylethynyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(3,3,3-trifluoroprop-1-ynyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-3-(3,3-difluoroprop-1-ynyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(phenylethynyl)thieno[3,2-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(3,3,3-trifluoroprop-1-ynyl)thieno[3,2-c]pyridine-5-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl]-2-(3,3-difluoroprop-1-ynyl)thieno[3,2-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-methyl-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-methyl-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-ethyl-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-ethyl-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-methyl-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-methylthio-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-methoxy-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-chloro-furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-vinylfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-cyanofuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-ethynylfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-cyanofuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-fluorofuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-chlorofuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-bromofuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-iodofuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-mercaptofuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylthio)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylamino)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(formylamino)furo[3,2-c]pyridine-6-carboxamide;-   2-(acetylamino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide;-   2-(acetyl(methyl)amino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(trifluoroacetyl)amino]furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(benzoylamino)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(diethylamino)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(diisopropylamino)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(pyrrolidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(morpholin-4-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(thiomorpholin-4yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperazin-1-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(4-methylpiperazin-1-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(cyclopropylamino)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[dimethylamino]furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(pyrrolidin-1-ylcarbonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperidin-1-ylcarbonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperazin-1-ylcarbonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(4-methylpiperazin-1-yl)carbonyl]furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(morpholin-4-ylcarbonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(thiomorpholin-4-ylcarbonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(aziridin-1-ylcarbonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(azetidin-1-ylcarbonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-formylfuro[3,2-c]pyridine-6-carboxamide;-   2-acetyl-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(trifluoroacetyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(phenyl)sulfonyl]lfuro[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylsulfonyl)furo[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-methyl-thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-methylthio-thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-methoxy-thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-4-chloro-thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-vinylthieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-ethynylthieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-prop-1-ynylthieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-cyanothieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-fluorothieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-chlorothieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-bromothieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-iodothieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethylthieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-mercaptothieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylthio)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(formylamino)thieno[3,2-c]pyridine-6-carboxamide;-   2-(acetylamino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[3,2-c]pyridine-6-carboxamide;-   2-(acetyl(methyl)amino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(trifluoroacetyl)amino]thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(benzoylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(diethylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(diisopropylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(pyrrolidin-1-yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperidin-1-yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(morpholin-4-yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(thiomorpholin-4yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperazin-1-yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(cyclopropylamino)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[dimethylamino]thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(pyrrolidin-1-ylcarbonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperidin-1-ylcarbonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperazin-1-ylcarbonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(4-methylpiperazin-1-yl)carbonyl]thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(morpholin-4-ylcarbonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(thiomorpholin-4-ylcarbonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(aziridin-1-ylcarbonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(azetidin-1-ylcarbonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-formylthieno[3,2-c]pyridine-6-carboxamide;-   2-acetyl-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(trifluoroacetyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(phenyl)sulfonyl]lthieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylsulfonyl)thieno[3,2-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-vinylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-methyl-furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-methoxy-furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-cyanofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-fluorofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-iodofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-mercaptofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(methylthio)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(methylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(formylamino)furo[2,3-c]pyridine-5-carboxamide;-   3-(acetylamino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   3-(acetyl(methyl)amino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[(trifluoroacetyl)amino]furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(benzoylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(diethylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(diisopropylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(morpholin-4-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(thiomorpholin-4yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperazin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(4-methylpiperazin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(cyclopropylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(pyrrolidin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperidin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperazin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[(4-methylpiperazin-1-yl)carbonyl]furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(morpholin-4-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(thiomorpholin-4-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(aziridin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(azetidin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-formylfuro[2,3-c]pyridine-5-carboxamide;-   3-acetyl-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(trifluoroacetyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[(phenyl)sulfonyl]lfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(methylsulfonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-ethyl-furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-ethynylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-cyanofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-fluorofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-bromofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-iodofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-mercaptofuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylthio)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(formylamino)furo[2,3-c]pyridine-5-carboxamide;-   2-(acetylamino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   2-(acetyl(methyl)amino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(trifluoroacetyl)amino]furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(benzoylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(diethylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(diisopropylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(morpholin-4-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(thiomorpholin-4yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperazin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(4-methylpiperazin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(cyclopropylamino)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(pyrrolidin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperidin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(piperazin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(4-methylpiperazin-1-yl)carbonyl]furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(morpholin-4-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(thiomorpholin-4-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(aziridin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(azetidin-1-ylcarbonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-formylfuro[2,3-c]pyridine-5-carboxamide;-   2-acetyl-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(trifluoroacetyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-[(phenyl)sulfonyl]lfuro[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-(methylsulfonyl)furo[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-methyl-thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-methylthio-thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-methoxy-thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-chloro-thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-vinylthieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-ethynylthieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-prop-1-ynylthieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-cyanothieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-fluorothieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-chlorothieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-bromothieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-iodothieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-trifluoromethylthieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-mercaptothieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(methylthio)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(methylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(formylamino)thieno[2,3-c]pyridine-5-carboxamide;-   3-(acetylamino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-c]pyridine-5-carboxamide;-   3-(acetyl(methyl)amino)-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[(trifluoroacetyl)amino]thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(benzoylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(diethylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(diisopropylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(pyrrolidin-1-yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperidin-1-yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(morpholin-4-yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(thiomorpholin-4yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperazin-1-yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(4-methylpiperazin-1-yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(cyclopropylamino)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[dimethylamino]thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(pyrrolidin-1-ylcarbonyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperidin-1-ylcarbonyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(piperazin-1-ylcarbonyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[(4-methylpiperazin-1-yl)carbonyl]thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(morpholin-4-ylcarbonyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(thiomorpholin-4-ylcarbonyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(aziridin-1-ylcarbonyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(azetidin-1-ylcarbonyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-formylthieno[2,3-c]pyridine-5-carboxamide;-   3-acetyl-N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(trifluoroacetyl)thieno[2,3-c]pyridine-5-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-[(phenyl)sulfonyl]lthieno[2,3-c]pyridine-5-carboxamide;    or-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-(methylsulfonyl)thieno[2,3-c]pyridine-5-carboxamide.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-furo[2,3-b]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-furo[2,3-b]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-furo[2,3-b]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-c]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-c]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-c]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-c]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-c]pyridine-2-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-2-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2    .2]oct-3-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide;    or-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-cyanofuro[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-fluorofuro[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-chlorofuro[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-bromofuro[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-iodofuro[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;-   2-(acetylamino)-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-(pyrrolidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-[dimethylamino]furo[3,2-c]pyridine-6-carboxamide;-   N-6-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-2,6-dicarboxamide;-   2-acetyl-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-6-carboxamide;-   methyl    6-{[1-(6-methyl)-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}furo[3,2-c]pyridine-2-carboxylate;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-vinylfuro[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-cyanofuro[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-fluorofuro[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-iodofuro[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;-   3-(acetylamino)-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;-   N-5-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-3,5-dicarboxamide;-   N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-formylfuro[2,3-c]pyridine-5-carboxamide;-   3-acetyl-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;-   methyl    5-{[1-(6-methyl)-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}furo[2,3-c]pyridine-3-carboxylate;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyanofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-fluorofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-chlorofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-bromofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-iodofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;-   2-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-(pyrrolidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-2-[dimethylamino]furo[3,2-c]pyridine-6-carboxamide;-   N-6-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-2,6-dicarboxamide;-   2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide;-   methyl    6-[(2-azabicyclo[2.2.1]hept-5-ylamino)carbonyl]furo[3,2-c]pyridine-2-carboxylate;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-vinylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyanofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-fluorofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-iodofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;-   3-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;-   N-5-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-3,5-dicarboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-3-formylfuro[2,3-c]pyridine-5-carboxamide;-   3-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide;-   methyl    5-[(2-azabicyclo[2.2.1]hept-5-ylamino)carbonyl]furo[2,3-c]pyridine-3-carboxylate;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyanofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-fluorofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-chlorofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-bromofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-iodofuro[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;-   2-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-(pyrrolidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-2-[dimethylamino]furo[3,2-c]pyridine-6-carboxamide;-   N-6-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-2,6-dicarboxamide;-   2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide;-   methyl    6-[2-azabicyclo[2.2.1]hept-6-ylamino)carbonyl]furo[3,2-c]pyridine-2-carboxylate;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-vinylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyanofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-fluorofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-iodofuro[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;-   3-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;-   N-5-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-3,5-dicarboxamide;-   N-(2-azabicyclo[2.2.1]hept-6-yl)-3-formylfuro[2,3-c]pyridine-5-carboxamide;-   3-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide;    or-   methyl    5-[2-azabicyclo[2.2.1]hept-6-ylamino)carbonyl]furo[2,3-c]pyridine-3-carboxylate.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   N-(1-azabicyclo[2.2.1]hept-3-yl)thieno[3,4-c]pyridine-6-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)thieno[3,4-c]pyridine-6-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[3,4-c]pyridine-6-carboxamide;    or-   N-(1-azabicyclo[3 2.2]non-3-yl)thieno[3,4-c]pyridine-6-carboxamide.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)thieno[3,4-c]pyridine-6-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)thieno[3,4-c]pyridine-6-carboxamide;    or-   N-(2-azabicyclo[2.2.1]hept-6-yl)thieno[3,4-c]pyridine-6-carboxamide.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   N-(1-azabicyclo[2.2.1]hept-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;-   N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;-   N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl][1]benzofuro[2,3-c]pyridine-3-carboxamide;    or-   N-[exo-4(S)-1-azabicyclo[2.2.1]hept-3-yl][1]benzothieno[2,3-c]pyridine-3-carboxamide.

The compound of Formula I, where the compound is any one or more orcombination of the following as the free base, or pharmaceutallyacceptable salt thereof as a pure enantiomer or racemic mixture thereof:

-   N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;-   N-(2-azabicyclo[2.2.1]hept-5-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;    or-   N-(2-azabicyclo[2.2.1]hept-6-yl)-benzothieno[3,2-c]pyridine-3-carboxamide.

A further embodiment of the present invention includes the compounds ofthe present invention, pharmaceutical compositions containing the activecompounds as the free base or as a pharmaceutically acceptable salt anda pharmaceutically acceptable carrier, and methods to treat theidentified diseases.

In another aspect, the invention includes treating a mammal sufferingfrom schizophrenia or psychosis by administering compounds of Formula Iin conjunction with antipsychotic drugs (also called anti-psychoticagents). The compounds of the present invention and the antipsychoticdrugs can be administered simultaneously or at separate intervals. Whenadministered simultaneously the compounds of the present invention andthe antipsychotic drugs can be incorporated into a single pharmaceuticalcomposition. Alternatively, two separate compositions, i.e., onecontaining compounds of the present invention and the other containingantipsychotic drugs, can be administered simultaneously.

A further embodiment of the present invention provides a methodcomprising administering a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositioncontains said compound to the mammal.

The present invention also includes a pharmaceutical compositioncomprising a compound of Formula I or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable excipient. The pharmaceuticalcomposition is administered rectally, topically, orally, sublingually,or parenterally for a therapeutically effective interval. Thepharmaceutical composition is administered to deliver a compound of thepresent invention in an amount of from about 0.001 to about 100 mg/kg ofbody weight of said mammal per day. The pharmaceutical composition isalso administered to deliver a compound of the present invention in anamount of from about 0.1 to about 50 mg/kg of body weight of said mammalper day.

A pharmaceutical composition comprising a compound of Formula I or apharmaceutically acceptable salt thereof, an anti-psychotic agent, and apharmaceutically acceptable excipient. The pharmaceutical composition isadministered to independently administer said compound and said agentrectally, topically, orally, sublingually, or parenterally for atherapeutically effective interval. The pharmaceutical composition isadministered to deliver a compound of the present invention in an amountof from about 0.001 to about 100 mg/kg of body weight of said mammal perday. The pharmaceutical composition is also administered to deliver acompound of the present invention in an amount of from about 0.1 toabout 50 mg/kg of body weight of said mammal per day.

The present invention also includes a use of a compound according toFormula I or pharmaceutically acceptable salt thereof for thepreparation of a medicament for treating a disease or condition, whereinthe mammal would receive symptomatic relief from the administration of atherapeutically effective amount of α7 nicotinic acetylcholine receptoragonist.

The present invention also includes a use of a compound according toFormula I or pharmaceutically acceptable salt thereof for thepreparation of a medicament for treating a disease or condition, whereinthe mammal would receive symptomatic relief from the administration of atherapeutically effective amount of α7 nicotinic acetylcholine receptoragonist, wherein the disease, or condition is any one or more orcombination of the following: cognitive and attention deficit symptomsof Alzheimer's, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, tardive dyskinesia,Pick's disease, dysregulation of food intake including bulemia andanorexia nervosa, withdrawal symptoms associated with smoking cessationand dependant drug cessation, Gilles de la Tourette's Syndrome,age-related macular degeneration, glaucoma, neurodegeneration associatedwith glaucoma, or symptoms associated with pain.

The present invention also includes a method for treating a disease orcondition in a mammal in need thereof, wherein the mammal would receivesymptomatic relief from the administration of an α7 nicotinicacetylcholine receptor agonist comprising administering to the mammal atherapeutically effective amount of a compound according to Formula I orpharmaceutically acceptable salt thereof.

The present invention also includes a method for treating a disease orcondition in a mammal in need thereof comprising administering to themammal a therapeutically effective amount of a compound according toFormula I or pharmaceutically acceptable salt thereof, wherein thedisease or condition is any one or more or combination of the following:cognitive and attention deficit symptoms of Alzheimer's,neurodegeneration associated with diseases such as Alzheimer's disease,pre-senile dementia (mild cognitive impairment), senile dementia,schizophrenia, psychosis, attention deficit disorder, attention deficithyperactivity disorder, depression, anxiety, general anxiety disorder,post traumatic stress disorder, mood and affective disorders,amyotrophic lateral sclerosis, borderline personality disorder,traumatic brain injury, behavioral and cognitive problems in general andassociated with brain tumors, AIDS dementia complex, dementia associatedwith Down's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, Parkinson's disease, tardive dyskinesia, Pick's disease,dysregulation of food intake including bulemia and anorexia nervosa,withdrawal symptoms associated with smoking cessation and dependant drugcessation, Gilles de la Tourette's Syndrome, age-related maculardegeneration, glaucoma, neurodegeneration associated with glaucoma, orsymptoms associated with pain.

The compounds of Formula I (Azabicyclo is I) have optically activecenters on the quinuclidine ring. The compounds of the present inventioninclude quinuclidines with the 3R configuration and also includesracemic mixtures, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purity. For example, and not bylimitation, compounds of Formula I include compounds withstereospecificity including:

The compounds of Formula I (Azabicyclo is II) have optically activecenter(s) on the [2.2.1] azabicyclic ring at C3 and C4. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purities of Formula I being endo-4S,endo-4R, exo-4S, exo-4R:

The endo isomer is the isomer where the non-hydrogen substituent at C3of the [2.2.1] azabicyclic compound is projected toward the larger ofthe two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-4(R), exo-4(S), endo4(R), andendo-4(S).

The compounds of Formula I (Azabicyclo III) have optically activecenter(s) on the [2.2.1] azabicyclic ring at C1, C4 and C5. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purities of Formula I being(1R,4R,5S), (1R,4R,5R), (1S,4S,5R), (1S,4S,5S):

The endo isomer is the isomer where the non-hydrogen substituent at C5of the [2.2.1] azabicyclic compound is projected toward the larger ofthe two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1R,4R,5S), exo-(1S,4S,5R),endo-(1S,4S,5S), endo-(1R,4R,5R).

The compounds of Formula I (Azabicyclo IV) have optically activecenter(s) on the [2.2.1] azabicyclic ring at C1, C4 and C6. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purities of Formula I beingexo-(1S,4R,6S), exo-(1R,4S,6R), endo-(1S,4R,6R), and endo-(1R,4S,6S):

The endo isomer is the isomer where the non-hydrogen substituent at C6of the [2.2.1] azabicyclic compound is projected toward the larger ofthe two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1S,4R,6S), exo-(1R,4S,6R),endo-(1S,4R,6R), and endo-(1R,4S,6S).

The compounds of Formula I (Azabicyclo is V) have optically activecenter(s) on the [3.2.1] azabicyclic ring at C3 and C5. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purifies of Formula I being endo-3S,5R, endo-3R, 5S, exo-3R, 5R, exo-3S, 5S:

The compounds of Formula I (Azabicyclo is VI) have optically activecenters on the [3.2.2] azabicyclic ring with one center being at C3 whenR₂ is absent. The scope of this invention includes racemic mixtures ofvarying degrees of stereochemical purities, the separate stereoisomers,and compositions of varying degrees of stereochemical purities ofFormula I being 3(S) and 3(R):

The compounds of the present invention having the specifiedstereochemistry have different levels of activity and that for a givenset of values for the variable substitutuents one isomer may bepreferred over the other isomers. Although it is desirable that thestereochemical purity be as high as possible, absolute purity is notrequired. This invention involves racemic mixtures and compositions ofvarying degrees of stereochemical purities when the Azabicyclo issubstituted with only the amide/thioamide or is substituted withsubstituents in addition to the amide/thioamide, e.g., R₂ is alkyl. Whenracemic mixtures and compositions are referenced, it is meant racemicmixtures and compositions of varying degrees of stereochemical purities.It is preferred to carry out stereoselective syntheses and/or to subjectthe reaction product to appropriate purification steps so as to producesubstantially enantiomerically pure materials. Suitable stereoselectivesynthetic procedures for producing enantiomerically pure materials arewell known in the art, as are procedures for purifying racemic mixturesinto enantiomerically pure fractions.

Stereoselective syntheses and/or subjecting the reaction product toappropriate purification steps produces substantially enantiomericallypure materials. Suitable stereoselective synthetic procedures forproducing enantiomerically pure materials are well known in the art, asare procedures for purifying racemic mixtures into enantiomerically purefractions.

Another embodiment of the compounds of Formula I includes any one ormore or combination of the following configurations for compounds:

-   -   where (i) the compound is a racemic mixture, or    -   (ii) the compound has the R stereochemistry at C-3 as discussed        herein and stereochemistry is unspecified at C-6.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

-   -   where (i) k₂ is 0 (R₂ is absent);    -   (ii) R₂ is alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, or aryl;    -   (iii) R₂ is alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, or aryl; or    -   (iv) the 2.2.1 moiety has the exo-4(S) stereochemistry as        discussed herein.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

-   -   where (i) R₂₋₃ is H;    -   (ii) R₂₋₃ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted        alkyl, cycloalkyl, or aryl; or    -   (iii) R₂₋₃ is alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, or aryl.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

-   -   where (i) R₂₋₃ is H;    -   (ii) R₂₋₃ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted        alkyl, cycloalkyl, or aryl; or    -   (iii) R₂₋₃ is alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, or aryl.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

-   -   where (i) k₅ is 0 (R₂ is absent);    -   (ii) R₂ is absent and where the Azabicyclo has the        stereochemistry of 3R, 5R;    -   (iii) k₅ is 2, where R_(2-a) is alkyl, halogenated alkyl,        substituted alkyl, cycloalkyl, or aryl, and where R_(2-b) is F,        Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, or aryl;    -   (iv) k₅ is 1, where R₂ is alkyl, halogenated alkyl, substituted        alkyl, cycloalkyl, or aryl; or    -   (v) k₅ is 1, where R₂ is F, Cl, Br, I, alkyl, halogenated alkyl,        substituted alkyl, cycloalkyl, or aryl.

Another embodiment of compounds of Formula I includes any one or more orcombination of the following configurations for compounds:

-   -   where (i) k₆ is 0 (R₂ is absent);    -   (ii) k₆ is 2, where each R_(2-a) is alkyl, halogenated alkyl,        substituted alkyl, cycloalkyl, or aryl and where each R_(2-b) is        F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, or aryl;    -   (iii) k₆ is 1, where R₂ is alkyl, halogenated alkyl, substituted        alkyl, cycloalkyl, or aryl; or    -   (iv) k₆ is 1, where R₂ is F, Cl, Br, I, alkyl, halogenated        alkyl, substituted alkyl, cycloalkyl, or aryl.

Further aspects and embodiments of the invention may become apparent tothose skilled in the art from a review of the following detaileddescription, taken in conjunction with the examples and the appendedclaims. While the invention is susceptible of embodiments in variousforms, described hereafter are specific embodiments of the inventionwith the understanding that the present disclosure is intended asillustrative, and is not intended to limit the invention to the specificembodiments described herein.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, we have found that compounds of Formula I:

-   -   wherein Azabicyclo is    -    provided that the bond between the —C(═X)— group and the W        group may be attached at any available carbon atom within the W        group as provided in R₃, R₆, and R₁₅;    -   X is O, or S;    -   R₀ is H, lower alkyl, substituted lower alkyl, or halogenated        lower alkyl;    -   Lower alkyl is both straight- and branched-chain moieties having        1-4 carbon atoms;    -   Halogenated lower alkyl is lower alkyl having 1 to (2 n+1)        substituent(s) independently selected from F, Cl, Br, or I where        n is the maximum number of carbon atoms in the moiety;    -   Substituted lower alkyl is lower alkyl having 0-3 substituents        independently selected from F, Cl, Br, or I and further having 1        substituent selected from —CN, —NO₂, —OR₁₀, —SR₁₀, —NR₁₀R₁₀,        —C(O)R₁₀, —C(O)OR₁₀, —C(S)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)N(R₁₀)₂,        —NR₁₀C(O)R₁₀, —S(O)R₁₀, —S(O)₂R₁₀, —OS(O)₂R₁₀, —S(O)₂NR₁₀R₁₀,        —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituent selected        from R₁₈ and further having 0-3 substituents independently        selected from F, Cl, Br, or I;    -   Each R₁ is H, alkyl, cycloalkyl, halogenated alkyl, substituted        phenyl, or substituted naphthyl;    -   Alkyl is both straight- and branched-chain moieties having from        1-6 carbon atoms;    -   Halogenated alkyl is an alkyl moiety having from 1-6 carbon        atoms and having 1 to (2 n+1) substituent(s) independently        selected from F, Cl, Br, or I, where n is the maximum number of        carbon atoms in the moiety;    -   Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon        atoms;    -   Substituted phenyl is a phenyl either having 1-4 substituents        independently selected from F, Cl, Br, or I, or having 1        substituent selected from R₁₂ and 0-3 substituents independently        selected from F, Cl, Br, or I;    -   Substituted naphthyl is a naphthalene moiety either having 1-4        substituents independently selected from F, Cl, Br, or I, or        having 1 substituent selected from R₁₂ and 0-3 substituents        independently selected from F, Cl, Br, or I, where the        substitution can be independently on either only one ring or        both rings of said naphthalene moiety;    -   Each R₂ is alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, aryl, F, Cl, Br, I, or R₂ is absent provided that        k₂, k₅, or k₆ is 0;    -   R₂₋₃ is H, alkyl, substituted alkyl, halogenated alkyl, F, Cl,        Br, or I;    -   Substituted alkyl is an alkyl moiety from 1-6 carbon atoms and        having 0-3 substituents independently selected from F, Cl, Br,        or I, and further having 1 substituent selected from R₇, R₉,        —CN, —NO₂, —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)OR₁₀,        —C(S)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀,        —S(O)R₁₀, —S(O)₂R₁₀, —OS(O)₂R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀,        phenyl, or phenyl having 1 substituent selected from R₁₈ and        further having 0-3 substituents independently selected from F,        Cl, Br, or I;    -   k₂ is 0 or 1;    -   k₅ and k₆ are independently 0, 1, or 2;    -   A---A′---A″ is N(R₄)—C(R₃)═C(R₃),        N═C(R₃)—C(R₁₅)₂—C(R₃)═C(R₃)—N(R₄),        C(R₃)₂—N(R₄)—C(R₃)₂—C(R₁₅)₂—C(R₃)═N, N(R₄)—C(R₃)₂—C(R₃)₂,        C(R₃)₂—C(R₃)₂—N(R₄), O—C(R₃)═C(R₃), O—C(R₃)₂—C(R₃)₂,        C(R₃)₂—O—C(R₃)₂, C(R₃)═C(R₃)—O, C(R₃)₂—C(R₃)₂—O, S—C(R₃)═C(R₃),        S—C(R₃)₂—C(R₃)₂, C(R₃)₂—S—C(R₃)₂, C(R₃)═C(R₃)—S, or        C(R₃)₂—C(R₃)₂—S;    -   Each R₃ is independently a bond to the core molecule provided        that only one R₃ and no R₆ or R₁₅ is also said bond, H, alkyl,        substituted alkyl, halogenated alkyl, alkenyl, substituted        alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl,        halogenated alkynyl, —CN, —NO₂, F, Br, Cl, I, —OR₁₉,        —C(O)N(R₁₀)₂, —N(R₁₀)₂, —SR₁₉, —S(O)₂R₁₉, —C(O)R₁₉,—CO₂R₁₉,        aryl, R₇, or R₉;    -   Aryl is phenyl, substituted phenyl, naphthyl, or substituted        naphthyl;    -   Alkenyl is straight- and branched-chain moieties having from 2-6        carbon atoms and having at least one carbon-carbon double bond;    -   Halogenated alkenyl is an unsaturated alkenyl moiety having from        2-6 carbon atoms and having 1 to (2 n−1) substituent(s)        independently selected from F, Cl, Br, or I, where n is the        maximum number of carbon atoms in the moiety;    -   Substituted alkenyl is an unsaturated alkenyl moiety having from        2-6 carbon atoms and having 0-3 substituents independently        selected from F, or Cl, and further having 1 substituent        selected from R₇, R₉, —CN, —NO₂, —OR₁₀, —SR₁₀, —NR₁₀R₁₀,        —C(O)R₁₀, —C(O)OR₁₀, —C(S)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)N(R₁₀)₂,        —NR₁₀C(O)R₁₀, —S(O)R₁₀, —S(O)₂R₁₀, —OS(O)₂R₁₀, —S(O)₂NR₁₀R₁₀,        —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituent selected        from R₁₈ and further having 0-3 substituents independently        selected from F, Cl, Br, or I;    -   Alkynyl is straight- and branched-chained moieties having from        2-6 carbon atoms and having at least one carbon-carbon triple        bond;    -   Halogenated alkynyl is an unsaturated alkynyl moiety having from        3-6 carbon atoms and having 1 to (2 n−3) substituent(s)        independently selected from F, Cl, Br, or I, where n is the        maximum number of carbon atoms in the moiety;    -   Substituted alkynyl is an unsaturated alkynyl moiety having from        3-6 carbon atoms and having 0-3 substituents independently        selected from F, or Cl, and further having 1 substituent        selected from R₇, R₉, —CN, —NO₂, —OR₁₀, —SR₁₀, —NR₁₀R₁₀,        —C(O)R₁₀, —C(O)OR₁₀, —C(S)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)N(R₁₀)₂,        —NR₁₀C(O)R₁₀, —S(O)R₁₀, —S(O)₂R₁₀, —OS(O)₂R₁₀, —S(O)₂NR₁₀R₁₀,        —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituent selected        from R₁₈ and further having 0-3 substituents independently        selected from F, Cl, Br, or I;    -   Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon        atoms and having 1-4 substituents independently selected from F,        or Cl;    -   Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon        atoms and having 0-3 substituents independently selected from F,        or Cl, and further having 1 substituent selected from R₇, R₉,        —CN, —NO₂, —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)OR₁₀,        —C(S)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀,        —S(O)R₁₀, —S(O)₂R₁₀, —OS(O)₂R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀,        phenyl, or phenyl having 1 substituent selected from R₁₈ and        further having 0-3 substituents independently selected from F,        Cl, Br, or I;    -   Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2        atoms within the ring being —S—, —N(R₁₇)—, or —O—;    -   Halogenated heterocycloalkyl is a cyclic moiety having from 4-7        atoms with 1-2 atoms within the ring being —S—, —N(R₁₇)—, or        —O—, and having 1-4 substituents independently selected from F,        or Cl;    -   Substituted heterocycloalkyl is a cyclic moiety having from 4-7        atoms with 1-2 atoms within the ring being —S—, —N(R₁₇)—, or —O—        and having 0-3 substituents independently selected from F, or        Cl, and further having 1 substituent selected from R₇, R₉, —CN,        —NO₂, —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)OR₁₀, —C(S)R₁₀,        —C(O)N(R₁₀)₂, —NR₁₀C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀, —S(O)R₁₀,        —S(O)₂R₁₀, —OS(O)₂R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or        phenyl having 1 substituent selected from R₁₈ and further having        0-3 substituents independently selected from F, Cl, Br, or I;    -   J, L, M, and Q are N or C(R₆) provided that only one of J, L, M,        or Q, is N and the others are C(R₆), further provided that when        the core molecule is attached to the pyridinyl moiety at M, Q is        C(H), and further provided that there is only one attachment to        the core molecule;    -   G and Y are C(R₆), provided that when the molecule is attached        to the phenyl moiety at Y, G is CH;    -   R₄ is H, alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,        heterocycloalkyl, halogenated heterocycloalkyl, substituted        heterocycloalkyl, R₇, or R₉;    -   Each R₅ is independently H, lower alkyl, or lower alkenyl;    -   Lower alkenyl is straight- and branched-chain moieties having        from 2-4 carbon atoms and having at least one carbon-carbon        double bond;    -   Each R₆ is independently H, F, Br, I, Cl, —CN, —CF₃, —OR₅, —SR₅,        —N(R₅)₂, or a bond to the core molecule provided that only one        R₆ and no R₃ or R₁₅ is said bond;    -   V is selected from O, S, or N(R₄);    -   R₇ is 5-membered heteroaromatic mono-cyclic moieties containing        within the ring 1-3 heteroatoms independently selected from the        group consisting of ═N—, —N(R₁₇)—, —O—, and —S—, and having 0-1        substituent selected from R₁₈ and further having 0-3        substituents independently selected from F, Cl, Br, or I, or R₇        is 9-membered fused-ring moieties having a 6-membered ring fused        to a 5-membered ring including the formula    -    wherein G₆ is O, S or NR₁₇,    -    wherein G is C(R₁₆) or N, and each G₂ and G₃ are independently        selected from C(R₁₆)₂, C(R₁₆), O, S, N, and N(R₁₈), provided        that both G₂ and G₃ are not simultaneously O, simultaneously S,        or simultaneously O and S, or    -    wherein G is C(R₁₆) or N, and each G₂ and G₃ are independently        selected from C(R₁₆)₂, C(R₁₆), O, S, N, and N(R₁₇), each        9-membered fused-ring moiety having 0-1 substituent selected        from R₁₈ and further having 0-3 substituent(s) independently        selected from F, Cl, Br, or I, wherein the R₇ moiety attaches to        other substituents as defined in formula I at any position on        either ring as valency allows;    -   Each R₈ is independently H, alkyl, halogenated alkyl,        substituted alkyl, cycloalkyl, halogenated cycloalkyl,        substituted cycloalkyl, heterocycloalkyl, halogenated        heterocycloalkyl, substituted heterocycloalkyl, R₇, R₉, phenyl,        or substituted phenyl;    -   R₉ is 6-membered heteroaromatic mono-cyclic moieties containing        within the ring 1-3 heteroatoms selected from ═N— and having 0-1        substituent selected from R₁₈ and 0-3 substituent(s)        independently selected from F, Cl, Br, or I, or R₉ is        10-membered heteroaromatic bi-cyclic moieties containing within        one or both rings 1-3 heteroatoms selected from ═N—, including,        but not limited to, quinolinyl or isoquinolinyl, each        10-membered fused-ring moiety having 0-1 substituent selected        from R₁₈ and 0-3 substituent(s) independently selected from F,        Cl, Br, or I, and having a bond directly or indirectly attached        to the core molecule where valency allows;    -   Each R₁₀ is independently H, alkyl, cycloalkyl,        heterocycloalkyl, alkyl substituted with 1 substituent selected        from R₁₃, cycloalkyl substituted with 1 substituent selected        from R₁₃, heterocycloalkyl substituted with 1 substituent        selected from R₁₃, halogenated alkyl, halogenated cycloalkyl,        halogenated heterocycloalkyl, phenyl, or substituted phenyl;    -   Each R₁₁ is independently H, alkyl, cycloalkyl,        heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or        halogenated heterocycloalkyl;    -   R₁₂ is —NO₂, —CN, alkyl, cycloalkyl, heterocycloalkyl,        halogenated alkyl, halogenated cycloalkyl, halogenated        heterocycloalkyl, substituted alkyl, substituted cycloalkyl,        substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁,        —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁;    -   R₁₃ is —CN, —CF₃, —NO₂, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁,        —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁,;    -   Each R₁₄ is H, alkyl, substituted alkyl, halogenated alkyl,        alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl,        substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, —CN,        —NO₂, —OR₁₉, —C(O)N(R₁₀)₂, —N(R₁₀)₂, —SR₁₉, —S(O)₂R₁₉, —C(O)R₁₉,        —CO₂R₁₉, aryl, R₇ or R₉;    -   Each R₁₅ is independently alkyl, substituted alkyl, halogenated        alkyl, alkenyl, substituted alkenyl, halogenated alkenyl,        alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I,        —CN, —NO₂, —OR₁₉, —C(O)N(R₁₀)₂, —N(R₁₀)₂, —SR₁₉, —CO₂R₁₉, aryl,        R₇, R₉, or a bond to the core molecule provided that only one        R₁₅ and no R₆ or R₃ is said bond;    -   Each R₁₆ is independently H, alkyl, cycloalkyl,        heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,        halogenated heterocycloalkyl, substituted alkyl, substituted        cycloalkyl, substituted heterocycloalkyl, F, Cl, Br, I, —NO₂,        —CN, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁,        —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, or a bond directly        or indirectly attached to the core molecule, provided that there        is only one said bond to the core molecule within the 9-membered        fused-ring moiety, further provided that the fused-ring moiety        has 0-1 substituent selected from alkyl, cycloalkyl,        heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,        halogenated heterocycloalkyl, substituted alkyl, substituted        cycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁,        —NR₁₁R₁₁, —C(O)R₁₁, —NO₂, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,        —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁, and further provided that the        fused-ring moiety has 0-3 substituent(s) selected from F, Cl,        Br, or I;    -   R₁₇ is H, alkyl, halogenated alkyl, substituted alkyl,        cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,        phenyl, —SO₂R₈, or phenyl having 1 substituent selected from R₁₈        and further having 0-3 substituents independently selected from        F, Cl, Br, or I;    -   R₁₈ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,        halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁₁,        —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,        —S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, —NO₂, alkyl substituted with 1-4        substituent(s) independently selected from F, Cl, Br, I, or R₁₃,        cycloalkyl substituted with 1-4 substituent(s) independently        selected from F, Cl, Br, I, or R₁₃, or heterocycloalkyl        substituted with 1-4 substituent(s) independently selected from        F, Cl, Br, I, or R₁₃;    -   R₁₉ is H, alkyl, cycloalkyl, substituted alkyl, halogenated        alkyl, substituted phenyl, or substituted naphthyl;    -   or pharmaceutical composition, pharmaceutically acceptable salt,        racemic mixture, or pure enantiomer thereof useful to treat any        one of or combination of cognitive and attention deficit        symptoms of Alzheimer's, neurodegeneration associated with        diseases such as Alzheimer's disease, pre-senile dementia (mild        cognitive impairment), senile dementia, schizophrenia,        psychosis, attention deficit disorder, attention deficit        hyperactivity disorder, mood and affective disorders,        amyotrophic lateral sclerosis, borderline personality disorder,        traumatic brain injury, behavioral and cognitive problems        associated with brain tumors, AIDS dementia complex, dementia        associated with Down's syndrome, dementia associated with Lewy        Bodies, Huntington's disease, depression, general anxiety        disorder, age-related macular degeneration, Parkinson's disease,        tardive dyskinesia, Pick's disease, post traumatic stress        disorder, dysregulation of food intake including bulemia and        anorexia nervosa, withdrawal symptoms associated with smoking        cessation and dependant drug cessation, Gilles de la Tourette's        Syndrome, glaucoma, neurodegeneration associated with glaucoma,        or symptoms associated with pain.

In another aspect, the invention includes methods of treating a mammalsuffering from schizophrenia or psychosis by administering compounds ofFormula I in conjunction with antipsychotic drugs (also calledantipsychotic agents). The compounds of Formula I and the antipsychoticdrugs can be administered simultaneously or at separate intervals. Whenadministered simultaneously the compounds of Formula I and theantipsychotic drugs can be incorporated into a single pharmaceuticalcomposition. Alternatively, two separate compositions, i.e., onecontaining compounds of Formula I and the other containing antipsychoticdrugs, can be administered simultaneously.

The present invention also includes the compounds of the presentinvention, pharmaceutical compositions containing the active compounds,and methods to treat the identified diseases.

Abbreviations which are well known to one of ordinary skill in the artmay be used (e.g., “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h”for hour or hours, “min” for minute or minutes, and “rt” for roomtemperature).

All temperatures are in degrees Centigrade.

Room temperature is within the range of 15-25 degrees Celsius.

AChR refers to acetylcholine receptor.

Pre-senile dementia is also known as mild cognitive impairment.

nAChR refers to nicotinic acetylcholine receptor.

5HT₃R refers to the serotonin-type 3 receptor.

α-btx refers to α-bungarotoxin.

FLIPR refers to a device marketed by Molecular Devices, Inc. designed toprecisely measure cellular fluorescence in a high throughput whole-cellassay. (Schroeder et. al., J. Biomolecular Screening, 1(2), p 75-80,1996).

TLC refers to thin-layer chromatography.

HPLC refers to high pressure liquid chromatography.

MeOH refers to methanol.

EtOH refers to ethanol.

IPA refers to isopropyl alcohol.

THF refers to tetrahydrofuran.

DMSO refers to dimethylsulfoxide.

DMF refers to dimethylformamide.

EtOAc refers to ethyl acetate.

Na₂SO₄ refers to sodium sulfate.

K₂CO₃ refers to potassium carbonate.

MgSO₄ refers to magnesium sulfate.

When Na₂SO₄, K₂CO₃, or MgSO₄ is used as a drying agent, it is anhydrous.

TMS refers to tetramethylsilane.

TEA refers to triethylamine.

DIEA refers to N,N-diisopropylethylamine.

MLA refers to methyllycaconitine.

Ether refers to diethyl ether.

HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N′, N′-tetramethyluroniumhexafluorophosphate.

DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

DPPA refers to diphenylphosphoryl azide.

50% saturated 1:1 NaCl/NaHCO₃ means a solution made by making a solutionof 1:1 saturated NaCl/NaHCO₃ and adding an equal volume of water.

CH₃SO₂Cl refers to methanesulfonyl chloride.

Halogen is F, Cl, Br, or I.

Non-inclusive examples of heteroaryl compounds that fall within thedefinition of R₇ and R₉ include, but are not limited to, thienyl,benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl,imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl,pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl,isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl,quinoxalinyl, naphthridinyl, furopyridinyl, pyrrolopyridinyl, orthienopyridinyl. All isomeric forms of the non-inclusive named moietiesare included, e.g., benzofuranyl includes 1-benzofuran-2-yl,1-benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5-yl,1-benzofuran-6-yl, 1-benzofuran-7-yl, 2-benzofuran-1-yl,2-benzofuran-2-yl, 2-benzofuran-3-yl, 2-benzofuran4-yl, or2-benzofuran-5-yl. The non-inclusive examples of R₇ and R₉ may besubstituted as allowed within the respective definition of R₇ and R₉ asvalency allows. One of ordinary skill in the art can identify theallowed substitution by comparing the non-inclusive examples with therespective definitions of R₇ and R₉.

Non-inclusive examples of heterocycloalkyl include, but are not limitedto, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino,piperidino, piperazine, azetidino, azetidinono, oxindolo,dihydroimidazolo, pyrrolidino, or isoxazolinyl.

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i-j) indicates a moietyof the integer “i” to the integer “j” carbon atoms, inclusive. Thus, forexample, C₁₋₆ alkyl refers to alkyl of one to six carbon atoms.

The core molecule is Azabicyclo-N(R₁)—C(═X)—:

Some of the amines described herein require the use of anamine-protecting group to ensure functionalization of the desirednitrogen. One of ordinary skill in the art would appreciate where,within the synthetic scheme to use said protecting group. Aminoprotecting group includes, but is not limited to, carbobenzyloxy (CBz),tert butoxy carbonyl (BOC) and the like. Examples of other suitableamino protecting groups are known to person skilled in the art and canbe found in “Protective Groups in Organic synthesis,” 3rd Edition,authored by Theodora Greene and Peter Wuts.

Mammal denotes human and other mammals.

Brine refers to an aqueous saturated sodium chloride solution.

Equ means molar equivalents.

IR refers to infrared spectroscopy.

Lv refers to leaving groups within a molecule, including Cl, OMe, OEt,or mixed anhydride.

Parr refers to the name of the company who sells the jars used forconducting reactions under pressure.

PSI means pound per square inch.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from TMS.

MS refers to mass spectrometry expressed as m/e or mass/charge unit.HRMS refers to high resolution mass spectrometry expressed as m/e ormass/charge unit. M+H⁺ refers to the positive ion of a parent plus ahydrogen atom. M−H⁻ refers to the negative ion of a parent minus ahydrogen atom. M+Na⁺ refers to the positive ion of a parent plus asodium atom. M+K⁺ refers to the positive ion of a parent plus apotassium atom. EI refers to electron impact. ESI refers to electrosprayionization. CI refers to chemical ionization. FAB refers to fast atombombardment.

Compounds of the present invention may be in the form ofpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalts” refers to salts prepared from pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases, and saltsprepared from inorganic acids, and organic acids. Salts derived frominorganic bases include aluminum, ammonium, calcium, ferric, ferrous,lithium, magnesium, potassium, sodium, zinc, and the like. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, such as arginine,betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, and the like. Salts derived from inorganic acids includesalts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, phosphorous acid and the like. Salts derived frompharmaceutically acceptable organic non-toxic acids include salts ofC₁₋₆ alkyl-carboxylic acids, di-carboxylic acids, and tri-carboxylicacids such as acetic acid, propionic acid, fumaric acid, succinic acid,tartaric acid, maleic acid, adipic acid, and citric acid, and aryl andalkyl sulfonic acids such as toluene sulfonic acids and the like.

By the term “effective amount” of a compound as provided herein is meanta nontoxic but sufficient amount of the compound(s) to provide thedesired effect. As pointed out below, the exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the disease that is beingtreated, the particular compound(s) used, the mode of administration,and the like. Thus, it is not possible to specify an exact “effectiveamount.” However, an appropriate effective amount may be determined byone of ordinary skill in the art using only routine experimentation.

The amount of therapeutically effective compound(s) that is administeredand the dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention depends on a variety offactors, including the age, weight, sex and medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the particular compound(s) employed, and thus mayvary widely. The compositions contain well know carriers and excipientsin addition to a therapeutically effective amount of compounds ofFormula I. The pharmaceutical compositions may contain active ingredientin the range of about 0.001-100 mg/kg/day for an adult, preferably inthe range of about 0.1-50 mg/kg/day for an adult. A total daily dose ofabout 1-1000 mg of active ingredient may be appropriate for an adult.The daily dose can be administered in one to four doses per day.

In addition to the compound(s) of Formula I, the composition fortherapeutic use may also comprise one or more non-toxic,pharmaceutically acceptable carrier materials or excipients. The term“carrier” material or “excipient” herein means any substance, not itselfa therapeutic agent, used as a carrier and/or diluent and/or adjuvant,or vehicle for delivery of a therapeutic agent to a subject or added toa pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropyl-methyl cellulose, orother methods known to those skilled in the art. For oraladministration, the pharmaceutical composition may be in the form of,for example, a tablet, capsule, suspension or liquid. If desired, otheractive ingredients may be included in the composition.

In addition to the oral dosing, noted above, the compositions of thepresent invention may be administered by any suitable route, in the formof a pharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compositions may, for example,be administered parenterally, e.g., intravascularly, intraperitoneally,subcutaneously, or intramuscularly. For parenteral administration,saline solution, dextrose solution, or water may be used as a suitablecarrier. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, benzylalcohol, sodium chloride, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart.

The serotonin type 3 receptor (5HT₃R) is a member of a superfamily ofligand-gated ion channels, which includes the muscle and neuronal nAChR,the glycine receptor, and the γ-aminobutyric acid type A receptor. Likethe other members of this receptor superfamily, the 5HT₃R exhibits alarge degree of sequence homology with α7 nAChR but functionally the twoligand-gated ion channels are very different. For example, α7 nAChR israpidly inactivated, is highly permeable to calcium and is activated byacetylcholine and nicotine. On the other hand, 5HT₃R is inactivatedslowly, is relatively impermeable to calcium and is activated byserotonin. These experiments suggest that the α7 nAChR and 5HT₃Rproteins have some degree of homology, but function very differently.Indeed the pharmacology of the channels is very different. For example,Ondansetron, a highly selective 5HT₃R antagonist, has little activity atthe α7 nAChR. The converse is also true. For example, GTS-21, a highlyselective α7 nAChR agonist, has little activity at the 5HT₃R.

α7 nAChR is a ligand-gated Ca⁺⁺ channel formed by a homopentamer of α7subunits. Previous studies have established that α-bungarotoxin (α-btx)binds selectively to this homopetameric, α7 nAChR subtype, and that α7nAChR has a high affinity binding site for both α-btx andmethyllycaconitine (MLA). α7 nAChR is expressed at high levels in thehippocampus, ventral tegmental area and ascending cholinergicprojections from nucleus basilis to thalamocortical areas. α7 nAChRagonists increase neurotransmitter release, and increase cognition,arousal, attention, learning and memory.

Data from human and animal pharmacological studies establish thatnicotinic cholinergic neuronal pathways control many important aspectsof cognitive function including attention, learning and memory (Levin,E. D., Psychopharmacology, 108:417-31, 1992; Levin, E. D. and Simon B.B., Psychopharmacology, 138:217-30, 1998). For example, it is well knownthat nicotine increases cognition and attention in humans. ABT-418, acompound that activates α4β2 and α7 nAChR, improves cognition andattention in clinical trials of Alzheimer's disease andattention-deficit disorders (Potter, A. et. al., Psychopharmacology(Berl)., 142(4):334-42, March 1999; Wilens, T. E. et. al., Am. J.Psychiatry, 156(12):1931-7, December 1999). It is also clear thatnicotine and selective but weak α7 nAChR agonists increase cognition andattention in rodents and non-human primates.

Schizophrenia is a complex multifactorial illness caused by genetic andnon-genetic risk factors that produce a constellation of positive andnegative symptoms. The positive symptoms include delusions andhallucinations and the negative symptoms include deficits in affect,attention, cognition and information processing. No single biologicalelement has emerged as a dominant pathogenic factor in this disease.Indeed, it is likely that schizophrenia is a syndrome that is producedby the combination of many low penetrance risk factors. Pharmacologicalstudies established that dopamine receptor antagonists are efficaciousin treating the overt psychotic features (positive symptoms) ofschizophrenia such as hallucinations and delusions. Clozapine, an“atypical” antipsychotic drug, is novel because it is effective intreating both the positive and some of the negative symptoms of thisdisease. Clozapine's utility as a drug is greatly limited becausecontinued use leads to an increased risk of agranulocytosis and seizure.No other antipsychotic drug is effective in treating the negativesymptoms of schizophrenia. This is significant because the restorationof cognitive functioning is the best predictor of a successful clinicaland functional outcome of schizophrenic patients (Green, M. F., Am JPsychiatry, 153:321-30, 1996). By extension, it is clear that betterdrugs are needed to treat the cognitive disorders of schizophrenia inorder to restore a better state of mental health to patients with thisdisorder.

One aspect of the cognitive deficit of schizophrenia can be measured byusing the auditory event-related potential (P50) test of sensory gating.In this test, electroencepholographic (EEG) recordings of neuronalactivity of the hippocampus are used to measure the subject's responseto a series of auditory “clicks” (Adler, L. E. et. al., Biol.Psychiatry, 46:8-18, 1999). Normal individuals respond to the firstclick with greater degree than to the second click. In general,schizophrenics and schizotypal patients respond to both clicks nearlythe same (Cullum, C. M. et. al., Schizophr. Res., 10:131-41, 1993).These data reflect a schizophrenic's inability to “filter” or ignoreunimportant information. The sensory gating deficit appears to be one ofthe key pathological features of this disease (Cadenhead, K. S. et. al.,Am. J. Psychiatry, 157:55-9, 2000). Multiple studies show that nicotinenormalizes the sensory deficit of schizophrenia (Adler, L. E. et. al.,Am. J. Psychiatry, 150:1856-61, 1993). Pharmacological studies indicatethat nicotine's effect on sensory gating is via the α7 nAChR (Adler, L.E. et. al., Schizophr. Bull., 24:189-202, 1998). Indeed, the biochemicaldata indicate that schizophrenics have 50% fewer of α7 nAChR receptorsin the hippocampus, thus giving a rationale to partial loss of α7 nAChRfunctionality (Freedman, R. et. al., Biol. Psychiatry, 38:22-33, 1995).Interestingly, genetic data indicate that a polymorphism in the promoterregion of the α7 nAChR gene is strongly associated with the sensorygating deficit in schizophrenia (Freedman, R. et. al., Proc. Nat'l Acad.Sci. USA, 94(2):587-92, 1997; Myles-Worsley, M. et. al., Am. J. Med.Genet, 88(5):544-50, 1999). To date, no mutation in the coding region ofthe α7 nAChR has been identified. Thus, schizophrenics express the sameα7 nAChR as non-schizophrenics.

Selective α7 nAChR agonists may be found using a functional assay onFLIPR (see WO 00/73431 A2). FLIPR is designed to read the fluorescentsignal from each well of a 96 or 384 well plate as fast as twice asecond for up to 30 minutes. This assay may be used to accuratelymeasure the functional pharmacology of α7 nAChR and 5HT₃R. To conductsuch an assay, one uses cell lines that expressed functional forms ofthe α7 nAChR using the α7/5-HT₃ channel as the drug target and celllines that expressed functional 5HT₃R. In both cases, the ligand-gatedion channel was expressed in SH-EP1 cells. Both ion channels can producerobust signal in the FLIPR assay.

The compounds of the present invention are α7 nAChR agonists and may beused to treat a wide variety of diseases. For example, they may be usedin treating schizophrenia, or psychosis.

Schizophrenia is a disease having multiple aspects. Currently availabledrugs are generally aimed at controlling the positive aspects ofschizophrenia, such as delusions. One drug, Clozapine, is aimed at abroader spectrum of symptoms associated with schizophrenia. This drughas many side effects and is thus not suitable for many patients. Thus,there is a need for a drug to treat the cognitive and attention deficitsassociated with schizophrenia. Similarly, there is a need for a drug totreat the cognitive and attention deficits associated withschizoaffective disorders, or similar symptoms found in the relatives ofschizophrenic patients.

Psychosis is a mental disorder characterized by gross impairment in thepatient's perception of reality. The patient may suffer from delusions,and hallucinations, and may be incoherent in speech. His behavior may beagitated and is often incomprehensible to those around him. hi the past,the term psychosis has been applied to many conditions that do not meetthe stricter definition given above. For example, mood disorders werenamed as psychoses.

There are a variety of antipsychotic drugs. The conventionalantipsychotic drugs include Chlorpromazine, Fluphenazine, Haloperidol,Loxapine, Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine,Thiothixene, and Trifluoperazine. These drugs all have an affinity forthe dopamine 2 receptor.

These conventional antipsychotic drugs have several side effects,including sedation, weight gain, tremors, elevated prolactin levels,akathisia (motor restlessness), dystonia and muscle stiffness. Thesedrugs may also cause tardive dyskinesia. Unfortunately, only about 70%of patients with schizophrenia respond to conventional antipsychoticdrugs. For these patients, atypical antipsychotic drugs are available.

Atypical antipsychotic drugs generally are able to alleviate positivesymptoms of psychosis while also improving negative symptoms of thepsychosis to a greater degree than conventional antipsychotics. Thesedrugs may improve neurocognitive deficits. Extrapyramidal (motor) sideeffects are not as likely to occur with the atypical antipsychoticdrugs, and thus, these atypical antipsychotic drugs have a lower risk ofproducing tardive dyskinesia. Finally these atypical antipsychotic drugscause little or no elevation of prolactin. Unfortunately, these drugsare not free of side effects. Although these drugs each producedifferent side effects, as a group the side effects include:agranulocytosis; increased risk of seizures, weight gain, somnolence,dizziness, tachycardia, decreased ejaculatory volume, and mildprolongation of QTc interval.

In a combination therapy to treat multiple symptoms of diseases such asschizophrenia, the compounds of Formula I and the anti-psychotic drugscan be administered simultaneously or at separate intervals. Whenadministered simultaneously the compounds of Formula I and theanti-psychotic drugs can be incorporated into a single pharmaceuticalcomposition, e.g., a pharmaceutical combination therapy composition.Alternatively, two separate compositions, i.e., one containing compoundsof Formula I and the other containing anti-psychotic drugs, can beadministered simultaneously. Examples of anti-psychotic drugs, inaddition to those listed above, include, but are not limited to,Thorazine, Mellaril, Trilafon, Navane, Stelazine, Permitil, Prolixin,Risperdal, Zyprexa, Seroquel, ZELDOX, Acetophenazine, Carphenazine,Chlorprothixene, Droperidol, Loxapine, Mesoridazine, Molindone,Ondansetron, Pimozide, Prochlorperazine, and Promazine.

A pharmaceutical combination therapy composition can includetherapeutically effective amounts of the compounds of Formula I and atherapeutically effective amount of anti-psychotic drugs. Thesecompositions may be formulated with common excipients, diluents orcarriers, and compressed into tablets, or formulated elixirs orsolutions for convenient oral administration or administered byintramuscular intravenous routes. The compounds can be administeredrectally, topically, orally, sublingually, or parenterally and maybeformulated as sustained relief dosage forms and the like.

When separately administered, therapeutically effective amounts ofcompositions containing compounds of Formula I and anti-psychotic drugsare administered on a different schedule. One may be administered beforethe other as long as the time between the two administrations fallswithin a therapeutically effective interval. A therapeutically effectiveinterval is a period of time beginning when one of either (a) thecompounds of Formula I, or (b) the anti-psychotic drugs is administeredto a human and ending at the limit of the beneficial effect in thetreatment of schizophrenia or psychosis of the combination of (a) and(b). The methods of administration of the compounds of Formula I and theanti-psychotic drugs may vary. Thus, either agent or both agents may beadministered rectally, topically, orally, sublingually, or parenterally.

As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, as another aspect of the present invention, thecompounds of the present invention may be used to treat a variety ofdiseases including cognitive and attention deficit symptoms ofAlzheimer's, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (also known as mild cognitiveimpairment), and senile dementia.

Alzheimer's disease has many aspects, including cognitive and attentiondeficits. Currently, these deficits are treated with cholinesteraseinhibitors. These inhibitors slow the break down of acetylcholine, andthereby provide a general nonspecific increase in the activity of thecholinergic nervous system. Since the drugs are nonspecific, they have awide variety of side effects. Thus, there is a need for a drug thatstimulates a portion of the cholinergic pathways and thereby providesimprovement in the cognitive and attention deficits associated withAlzheimer's disease without the side effects created by nonspecificstimulation of the cholinergic pathways.

Neurodegeneration is a common problem associated with diseases such asAlzheimer's disease. While the current drugs treat some of the symptomsof this disease, they do not control the underlying pathology of thedisease. Accordingly, it would be desirable to provide a drug that canslow the progress of Alzheimer's disease.

Pre-senile dementia (mild cognitive impairment) concerns memoryimpairment rather than attention deficit problems and otherwiseunimpaired cognitive functioning. Mild cognitive impairment isdistinguished from senile dementia in that mild cognitive impairmentinvolves a more persistent and troublesome problem of memory loss forthe age of the patient. There currently is no medication specificallyidentified for treatment of mild cognitive impairment, due somewhat tothe newness of identifying the disease. Therefore, there is a need for adrug to treat the memory problems associated with mild cognitiveimpairment.

Senile dementia is not a single disease state. However, the conditionsclassified under this name frequently include cognitive and attentiondeficits. Generally, these deficits are not treated. Accordingly, thereis a need for a drug that provides improvement in the cognitive andattention deficits associated with senile dementia.

As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, yet other diseases to be treated with compounds ofthe present invention include treating the cognitive and attentiondeficits as well as the neurodegeneration associated with any one ormore or combination of the following: attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problemsassociated with brain tumors, AIDS dementia complex, dementia associatedwith Down's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, Parkinson's disease, tardive dyskinesia, Pick's disease,dysregulation of food intake including bulemia and anorexia nervosa,withdrawal symptoms associated with smoking cessation and dependant drugcessation, Gilles de la Tourette's Syndrome, age-related maculardegeneration, glaucoma, neurodegeneration associated with glaucoma, orsymptoms associated with pain.

Attention deficit disorder is generally treated with methylphenidate, anamphetamine-like molecule that has some potential for abuse.Accordingly, it would be desirable to provide a drug that treatsattention deficit disorder while having fewer side effects than thecurrently used drug.

Attention deficit hyperactivity disorder, otherwise known as ADHD, is aneurobehavioral disorder affecting 3-5% of all American children. ADHDconcerns cognitive alone or both cognitive and behavioral actions byinterfering with a person's ability to stay on a task and to exerciseage-appropriate inhibition. Several types of ADHD exist: a predominantlyinattentive subtype, a predominantly hyperactive-impulsive subtype, anda combined subtype. Treatment may include medications such asmethylphenidate, dextroamphetamine, or pemoline, which act to decreaseimpulsivity and hyperactivity and to increase attention. No “cure” forADHD currently exists. Children with the disorder seldom outgrow it;therefore, there is a need for appropriate medicaments.

Depression is a mood disorder of varying lengths of normally severalmonths to more than two years and of varying degrees of feelingsinvolving sadness, despair, and discouragement. The heterocyclicantidepressants (HCA's) are currently the largest class ofantidepressants, but monoamine oxidase inhibitors (MAOI's) are used inparticular types of depression. Common side effects from HCA's aresedation and weight gain. In elderly patients with organic braindisease, the side effects from HCA's can also include seizures andbehavioral symptoms. The main side effects from using MAOI's occur fromdietary and drug interactions. Therefore, agents with fewer side effectswould be useful.

Anxiety disorders (disorders with prominent anxiety or phobicavoidance), represent an area of umet medical needs in the treatment ofpsychiatric illness. See Diagnostic & Statistical Manual of MentalDisorders, IV (1994), pp 393-394, for various disease forms of anxiety.

General anxiety disorder (GAD) occurs when a person worries about thingssuch as family, health, or work when there is no reason to worry and isunable not to worry. About 3 to 4% of the U.S. population has GAD duringthe course of a year. GAD most often strikes people in childhood oradolescence, but can begin in adulthood, too. It affects women moreoften than men. Currently, treatment involves cognitive-behavioraltherapy, relaxation techniques, and biofeedback to control muscletension and medications such as benzodiazepines, imipramine, andbuspirone. These drugs are effective but all have side-effectliabilities. Therefore, there is a need of a pharmaceutical agent toaddress the symptoms with fewer side effects.

Anxiety also includes post-traumatic stress disorder (PTSD), which is aform of anxiety triggered by memories of a traumatic event that directlyaffected the patient or that the patient may have witnessed. Thedisorder commonly affects survivors of traumatic events including sexualassault, physical assault, war, torture, natural disasters, anautomobile accident, an airplane crash, a hostage situation, or a deathcamp. The affliction also can affect rescue workers at an airplane crashor a mass shooting, someone who witnessed a tragic accident or someonewho has unexpectedly lost a loved one. Treatment for PTSD includescognitive-behavioral therapy, group psychotherapy, and medications suchas Clonazepam, Lorazepam and selective serotonin-reuptake inhibitorssuch as Fluoxetine, Sertraline, Paroxetine, Citalopram and Fluvoxamine.These medications help control anxiety as well as depression. Variousforms of exposure therapy (such as systemic desensitization and imaginalflooding) have all been used with PTSD patients. Exposure treatment forPTSD involves repeated reliving of the trauma, under controlledconditions, with the aim of facilitating the processing of the trauma.Therefore, there is a need for better pharmaceutical agents to treatpost traumatic stress disorder.

Mood and affective disorders fall within a large group of diseases,including monopolar depression and bi-polar mood disorder. Thesediseases are treated with three major classes of compounds. The firstgroup is the heterocyclic antidepressant (HCA's). This group includesthe well-known tricyclic antidepressants. The second group of compoundsused to treat mood disorders is the monoamine oxidase inhibitors(MAOI's) that are used in particular types of diseases. The third drugis lithium. Common side effects from HCA's are sedation and weight gain.In elderly patients with organic brain disease, the side effects ofHCA's can also include seizures and behavioral symptoms. The main sideeffects from using MAOI's occur from dietary and drug interactions.Benign side effects from the use of lithium include, but are not limitedto, weight gain, nausea, diarrhea, polyuria, polydipsia, and tremor.Toxic side effects from lithium can include persistent headache, mentalconfusion, and may reach seizures and cardiac arrhythmias. Therefore,agents with less side effects or interactions with food or othermedications would be useful.

Borderline personality disorder, although not as well known as bipolardisorder, is more common. People having borderline personality disordersuffer from a disorder of emotion regulation. Pharmaceutical agents areused to treat specific symptoms, such as depression or thinkingdistortions.

Acquired immune deficiency syndrome (AIDS) results from an infectionwith the human immunodeficiency virus (HIV). This virus attacks selectedcells and impairs the proper function of the immune, nervous, and othersystems. HIV infection can cause other problems such as, but not limitedto, difficulties in thinking, otherwise known as AIDS dementia complex.Therefore, there is a need to drugs to relieve the confusion and mentaldecline of persons with AIDS.

Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease,belongs to a class of disorders known as motor neuron diseases whereinspecific nerve cells in the brain and spinal cord gradually degenerateto negatively affect the control of voluntary movement. Currently, thereis no cure for amyotrophic lateral sclerosis although patients mayreceive treatment from some of their symptoms and although Riluzole hasbeen shown to prolong the survival of patients. Therefore, there is aneed for a pharmaceutical agent to treat this disease.

Traumatic brain injury occurs when the brain is damaged from a suddenphysical assault on the head. Symptoms of the traumatic brain injuryinclude confusion and other cognitive problems. Therefore, there is aneed to address the symptoms of confusion and other cognitive problems.

Brain tumors are abnormal growths of tissue found inside of the skull.Symptoms of brain tumors include behavioral and cognitive problems.Surgery, radiation, and chemotherapy are used to treat the tumor, butother agents are necessary to address associated symptoms. Therefore,there is a need to address the symptoms of behavioral and cognitiveproblems.

Persons with Down's syndrome have in all or at least some of their cellsan extra, critical portion of the number 21 chromosome. Adults who haveDown's syndrome are known to be at risk for Alzheimer-type dementia.Currently, there is no proven treatment for Down's syndrome. Therefore,there is a need to address the dementia associated with Down's syndrome.

Genetically programmed degeneration of neurons in certain areas of thebrain cause Huntington's disease. Early symptoms of Huntington's diseaseinclude mood swings, or trouble learning new things or remembering afact. Most drugs used to treat the symptoms of Huntington's disease haveside effects such as fatigue, restlessness, or hyperexcitability.Currently, there is no treatment to stop or reverse the progression ofHuntington's disease. Therefore, there is a need of a pharmaceuticalagent to address the symptoms with fewer side effects.

Dementia with Lewy Bodies is a neurodegenerative disorder involvingabnormal structures known as Lewy bodies found in certain areas of thebrain. Symptoms of dementia with Lewy bodies include, but are notlimited to, fluctuating cognitive impairment with episodic delirium.Currently, treatment concerns addressing the parkinsonian andpsychiatric symptoms. However, medicine to control tremors or loss ofmuscle movement may actually accentuate the underlying disease ofdementia with Lewy bodies. Therefore, there is a need of apharmaceutical agent to treat dementia with Lewy bodies.

Parkinson's disease is a neurological disorder characterized by tremor,hypokinesia, and muscular rigidity. Currently, there is no treatment tostop the progression of the disease. Therefore, there is a need of apharmaceutical agent to address Parkinson's.

Tardive dyskinesia is associated with the use of conventionalantipsychotic drugs. This disease is characterized by involuntarymovements most often manifested by puckering of the lips and tongueand/or writhing of the arms or legs. The incidence of tardive dyskinesiais about 5% per year of drug exposure among patients taking conventionalantipsychotic drugs. In about 2% of persons with the disease, tardivedyskinesia is severely disfiguring. Currently, there is no generalizedtreatment for tardive dyskinesia. Furthermore, the removal of theeffect-causing drugs is not always an option due to underlying problems.Therefore, there is a need for a pharmaceutical agent to address thesymptoms of tardive dyskinesia.

Pick's disease results from a slowly progressive deterioration of socialskills and changes in personality with the resulting symptoms beingimpairment of intellect, memory, and language. Common symptoms includememory loss, lack of spontaneity, difficulty in thinking orconcentrating, and speech disturbances. Currently, there is no specifictreatment or cure for Pick's disease but some symptoms can be treatedwith cholinergic and serotonin-boosting antidepressants. In addition,antipsychotic medications may alleviate symptoms in FTD patients who areexperiencing delusions or hallucinations. Therefore, there is a need fora pharmaceutical agent to treat the progressive deterioration of socialskills and changes in personality and to address the symptoms with fewerside effects.

Dysregulation of food intake associated with eating disease, includingbulemia nervosa and anorexia nervosa, involve neurophysiologicalpathways. Anorexia nervosa is hard to treat due to patients not enteringor remaining in after entering programs. Currently, there is noeffective treatment for persons suffering from severe anorexia nervosa.Cognitive behavioral therapy has helped patients suffering from bulemianervosa; however, the response rate is only about 50% and currenttreatment does not adequately address emotional regulation. Therefore,there is a need for pharmaceutical agents to address neurophysiologicalproblems underlying diseases of dysregulation of food intake.

Cigarette smoking has been recognized as a major public health problemfor a long time. However, in spite of the public awareness of healthhazard, the smoking habit remains extraordinarily persistent anddifficult to break. There are many treatment methods available, and yetpeople continue to smoke. Administration of nicotine transdermally, orin a chewing gum base is common treatments. However, nicotine has alarge number of actions in the body, and thus can have many sideeffects. It is clear that there is both a need and a demand of longstanding for a convenient and relatively easy method for aiding smokersin reducing or eliminating cigarette consumption. A drug that couldselectively stimulate only certain of the nicotinic receptors would beuseful in smoke cessation programs.

Smoke cessation programs may involve oral dosing of the drug of choice.The drug may be in the form of tablets. However, it is preferred toadminister the daily dose over the waking hours, by administration of aseries of incremental doses during the day. The preferred method of suchadministration is a slowly dissolving lozenge, troche, or chewing gum,in which the drug is dispersed. Another drug in treating nicotineaddiction is Zyban. This is not a nicotine replacement, as are the gumand patch. Rather, this works on other areas of the brain, and itseffectiveness is to help control nicotine craving or thoughts aboutcigarette use in people trying to quit. Zyban is not very effective andeffective drugs are needed to assist smokers in their desire to stopsmoking. These drugs may be administered transdermally through the useof skin patches. In certain cases, the drugs may be administered bysubcutaneous injection, especially if sustained release formulations areused.

Drug use and dependence is a complex phenomenon, which cannot beencapsulated within a single definition. Different drugs have differenteffects, and therefore different types of dependence. Drug dependencehas two basic causes, that is, tolerance and physical dependence.Tolerance exists when the user must take progressively larger doses toproduce the effect originally achieved with smaller doses. Physicaldependence exists when the user has developed a state of physiologicadaptation to a drug, and there is a withdrawal (abstinence) syndromewhen the drug is no longer taken. A withdrawal syndrome can occur eitherwhen the drug is discontinued or when an antagonist displaces the drugfrom its binding site on cell receptors, thereby counteracting itseffect. Drug dependence does not always require physical dependence.

In addition drug dependence often involves psychological dependence,that is, a feeling of pleasure or satisfaction when taking the drug.These feelings lead the user to repeat the drug experience or to avoidthe displeasure of being deprived of the drug. Drugs that produce strongphysical dependence, such as nicotine, heroin and alcohol are oftenabused, and the pattern of dependence is difficult to break. Drugs thatproduce dependence act on the CNS and generally reduce anxiety andtension; produce elation, euphoria, or other pleasurable mood changes;provide the user feelings of increased mental and physical ability; oralter sensory perception in some pleasurable manner. Among the drugsthat are commonly abused are ethyl alcohol, opioids, anxiolytics,hypnotics, cannabis (marijuana), cocaine, amphetamines, andhallucinogens. The current treatment for drug-addicted people ofteninvolves a combination of behavioral therapies and medications.Medications, such as methadone or LAAM (levo-alpha-acetyl-methadol), areeffective in suppressing the withdrawal symptoms and drug cravingassociated with narcotic addiction, thus reducing illicit drug use andimproving the chances of the individual remaining in treatment. Theprimary medically assisted withdrawal method for narcotic addiction isto switch the patient to a comparable drug that produces milderwithdrawal symptoms, and then gradually taper off the substitutemedication. The medication used most often is methadone, taken orallyonce a day. Patients are started on the lowest dose that prevents themore severe signs of withdrawal and then the dose is gradually reduced.Substitutes can be used also for withdrawal from sedatives. Patients canbe switched to long-acting sedatives, such as diazepam or phenobarbital,which are then gradually reduced.

Gilles de la Tourette's Syndrome is an inherited neurological disorder.The disorder is characterized by uncontrollable vocal sounds called ticsand involuntary movements. The symptoms generally manifest in anindividual before the person is 18 years of age. The movement disordermay begin with simple tics that progress to multiple complex tics,including respiratory and vocal ones. Vocal tics may begin as gruntingor barking noises and evolve into compulsive utterances. Coprolalia(involuntary scatologic utterances) occurs in 50% of patients. Severetics and coprolalia may be physically and socially disabling. Tics tendto be more complex than myoclonus, but less flowing than choreicmovements, from which they must be differentiated. The patient mayvoluntarily suppress them for seconds or minutes.

Currently simple tics are often treated with benzodiazepines. For simpleand complex tics, Clonidine may be used. Long-term use of Clonidine doesnot cause tardive dyskinesia; its limiting adverse effect ishypotension. In more severe cases, antipsychotics, such as Haloperidolmay be required, but side effects of dysphoria, parkinsonism, akathisia,and tardive dyskinesia may limit use of such antipsychotics. There is aneed for safe and effective methods for treating this syndrome.

Age-related macular degeneration (AMD) is a common eye disease of themacula which is a tiny area in the retina that helps produce sharp,central vision required for “straight ahead” activities that includereading and driving. Persons with AMD lose their clear, central vision.AMD takes two forms: wet and dry. In dry AMD, there is a slow breakdownof light-sensing cells in the macula. There currently is no cure for dryAMD. In wet AMD, new, fragile blood vessels growing beneath the maculaas dry AMD worsens and these vessels often leak blood and fluid to causerapid damage to the macula quickly leading to the loss of centralvision. Laser surgery can treat some cases of wet AMD. Therefore, thereis a need of a pharmaceutical agent to address AMD.

Glaucoma is within a group of diseases occurs from an increase inintraocular pressure causing pathological changes in the optical diskand negatively affects the field of vision. Medicaments to treatglaucoma either decrease the amount of fluid entering the eye orincrease drainage of fluids from the eye in order to decreaseintraocular pressure. However, current drugs have drawbacks such as notworking over time or causing side effects so the eye-care professionalhas to either prescribe other drugs or modify the prescription of thedrug being used. There is a need for safe and effective methods fortreating problems manifesting into glaucoma.

Ischemic periods in glaucoma cause release of excitotoxic amino acidsand stimulate inducible form of nitric oxide synthase (iNOS) leading toneurodegeneration. Alpha 7 nicotinic agonists may stimulate the releaseof inhibitory amino acids such as GABA which will dampenhyperexcitablity. Alpha 7 nicotinic agonists are also directlyneuroprotective on neuronal cell bodies. Thus alpha 7 nicotinic agonistshave the potential to be neuroprotective in glaucoma.

Persons afflicted with pain often have what is referred to as the“terrible triad” of suffering from the pain, resulting in sleeplessnessand sadness, all of which are hard on the afflicted individual and thatindividual's family. Pain can manifest itself in various forms,including, but not limited to, headaches of all severity, back pain,neurogenic, and pain from other ailments such as arthritis and cancerfrom its existence or from therapy to irradicate it. Pain can be eitherchronic (persistent pain for months or years) or acute (short-lived,immediate pain to inform the person of possible injury and need oftreatment). Persons suffering from pain respond differently toindividual therapies with varying degrees of success. There is a needfor safe and effective methods for treating pain.

Finally, the compounds of the present invention may be used incombination therapy with typical and atypical anti-psychotic drugs (alsocalled an anti-psychotic agent). All compounds within the presentinvention are useful for and may also be used in combination with eachother to prepare pharmaceutical compositions. Such combination therapylowers the effective dose of the anti-psychotic drug and thereby reducesthe side effects of the anti-psychotic drugs. Some typicalanti-psychotic drugs that may be used in the practice of the inventioninclude Haldol. Some atypical anti-psychotic drugs include Ziprasidone,Olanzapine, Resperidone, and Quetiapine.

Compounds of Formula I can be prepared as shown in Scheme 1. The keystep in the preparation of this class of compounds is the coupling of anazabicyclic moiety with the requisite acid chloride (Lv=Cl), mixedanhydride (e.g., Lv=diphenyl phosphoryl,bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formulaof O—C(O—R_(Lv), where R_(Lv) includes phenyl or t-butyl), or carboxylicacid (Lv=OH) in the presence of an activating reagent. Suitableactivating reagents are well known in the art, for examples see Kiso,Y., Yajima, H. “Peptides” pp. 39-91, San Diego, Calif., Academic Press,(1995), and include, but are not limited to, agents such ascarbodiimides, phosphonium and uronium salts (such as HATU).

Generally, the acid is activated using HATU or is converted to the acylazide by using DPPA. The appropriate Azabicyclo-amine is added to asolution of the appropriate activated acid or azide to give the desiredfinal compounds. Or, the acid is converted into a mixed anhydride bytreatment with bis (2-oxo-3-oxazolidinyl) phosphinic chloride in thepresence of TEA with CH₂Cl₂ or CHCl₃ as the solvent. The resultinganhydride solution is directly reacted with the appropriate amine addedneat or using DMF or aqueous DMF as solvent. In some cases, the ester(Lv being OMe or OEt) may be reacted directly with the amine inrefluxing methanol or ethanol to give the compounds of Formula I.

There are several methods by which the amine precursor for Azabicyclo Ican be obtained. Certain 6-substituted-[2.2.2]-3-amines are known in theart. The preparation of compounds of Azabicyclo I is described in ActaPol. Pharm. 179-85 (1981). Altematively, the6-substituted-[2.2.2]-3-amine can be prepared by reduction of an oximeor an imine of the corresponding 6-substituted-3-quinuclidinone bymethods known to one of ordinary skill in the art (see J. LabelledCompds. Radiopharm., 53-60 (1995), J. Med. Chem. 988-995, (1998), Synth.Commun. 1895-1911 (1992), Synth. Commun. 2009-2015 (1996)).Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared from a6-substituted-3-hydroxyquinuclidine by Mitsunobu reaction followed bydeprotection as described in Synth. Commun. 1895-1911 (1995).Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared byconversion of a 6-substituted-3-hydroxyquinuclidine into thecorresponding mesylate or tosylate, followed by displacement with sodiumazide and reduction as described in J. Med. Chem. 587-593 (1975).

The oximes can be prepared by treatment of the 3-quinuclidinones withhydroxylamine hydrochloride in the presence of base. The imines can beprepared by treatment of the 3-quinuclidinones with a primary amineunder dehydrating conditions. The 3-hydroxyquinuclidines can be preparedby reduction of the 3-quinuclidinones. The6-substituted-3-quinuclidinones can be prepared by known procedures (seeJ. Gen. Chem. Russia 3791-3795, (1963), J. Chem. Soc. Perkin Trans. I409-420 (1991), J. Org. Chem. 3982-3996 (2000)).

One of ordinary skill in the art will recognize that the methodsdescribed for the reaction of the unsubstituted3-amino-1-azabicyclo[2.2.1]heptane (Azabicyclo II where R₂ is absent)are equally applicable to substituted compounds (R₂ is present and isother than H). The compounds where R₂ is other than H can be preparedfrom appropriately substituted nitro alcohols using procedures describedin Tetrahedron (1997), 53, p. 11121 as shown below. Methods tosynthesize nitro alcohols are well known in the art (see J. Am. Chem.Soc. (1947), 69, p 2608). The scheme below is a modification of thesynthesis of exo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt, described in detail herein, to show how toobtain these amine precursors. The desired salt can be made usingstandard procedures.

Compounds for Azabicyclo II where R₂ is other than H can also beprepared by modification of intermediates described in the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt, described in detail herein. For example,Int 6 can be oxidized to the aldehyde and treated with an organometallicreagent to provide Int 20 using procedures described in Tetrahedron(1999), 55, p 13899. Int 20 can be converted into the amine usingmethods described for the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt. Once the amine is obtained, the desiredsalt can be made using standard procedures.

The schemes used are for making exo-3-amino-1-azabicyclo[2.2.1]heptane.However, the modifications discussed are applicable to make the endoisomer also.

N-(2-azabicyclo[2.2.1]hept)-5-amine and 6-amine:

where Lv can be —CH₂Ph, —CH(Me)Ph, —OH, —OMe, or —OCH₂Ph.

The respective amine precursors for Azabicyclo III and Azabicyclo IV canbe prepared by reduction of an oxime or an imine of the correspondingN-2-azabicyclo[2.2.1]-heptanone by methods known to one skilled in theart (see J. Labelled Compds. Radiopharm., 53-60 (1995), J. Med. Chem.988-995, (1998), Synth. Commun. 1895-1911 (1992), Synth. Commun.2009-2015 (1996)). The oximes can be prepared by treatment of theN-2-azabicyclo[2.2.1]heptanones with hydroxylamine hydrochloride in thepresence of a base. The imines can be prepared by treatment of theN-2-azabicyclo[2.2.1]-heptanones with a primary amine under dehydratingconditions. The N-2-azabicyclo[2.2.1]heptanones can be prepared by knownprocedures (see Tet. Lett. 1419-1422 (1999), J. Med. Chem. 2184-2191(1992), J. Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)).

One of ordinary skill in the art will also recognize that the methodsdescribed for the reaction of the unsubstituted1-azabicyclo[3.2.1]octan-3-amine or 1-azabicyclo[3.2.2]nonan-3-amine (R₂is absent) are equally applicable to substituted compounds (R₂ is otherthan H) (Azabicyclo is V and VI, respectively). The R₂ substituent maybe introduced as known to one skilled in the art through standardalkylation chemistry. Exposure of 1-azabicyclo[3.2.1]octan-3-one or1-azabicyclo[3.2.2]nonan-3-one to a hindered base such as LDA (lithiumdiisopropylamide) in a solvent such as THF or ether between 0° C. to−78° C. followed by the addition of an alkylating agent (R₂Lv, whereLv=Cl, Br, I, OTs, etc.) will, after being allowed to warm to about 0°C. to rt followed by an aqueous workup, provide the desired compound asa mixture of isomers. Chromatographic resolution (flash, HPLC, or chiralHPLC) will provided the desired purified alkylated ketones. From there,formation of the oxime and subsequent reduction will provide the desiredstereoisomers.

Thioamides can be prepared from the requisite thioester by directdisplacement of the thioester with an aminoazabicyclic compound. Thethioester can be prepared as described in J. Organometallic Chem., 95-98(1987). One of ordinary skill in the art would quickly identify thatsaid compounds could also be prepared directly from the amidesexemplified herein by direct treatment with a reagent such andLawesson's reagent (see Lawesson et. al. in Bull. Soc. Chim. Belg., 229(1978)) or P₄S₁₀ (see Chem. Rev., 45 (1961)). Alternatively one canreact a dithiocarboxylic ester with the corresponding amino-azabicyclocompound to form the same thioamide.

Preparation of the Amines:

Synthesis of exo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt:

Step A. Preparation of 2-(benzoyloxy)-1-nitroethane (Int 1).

Benzoyl chloride (14.9 mL, 128 mmol) is added to a stirred solution ofnitroethanol (9.2 mL, 128 mmol) in dry benzene (120 mL). The solution isrefluxed for 24 hr and then concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withhexanes-EtOAc (80:20) affords Int 1 as a white solid (68% yield): ¹H NMR(CDCl₃) δ8.0, 7.6, 7.4, 4.9, 4.8.

Step B. Preparation of ethyl E4-(benzylamino)-2-butenoate (Int 2).

Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is added to astirred solution of benzylamine (16 mL, 146 mmol) in CH₂Cl₂ (200 mL) atrt. The reaction mixture stirs for 15 min, and is diluted with ether (1L). The mixture is washed with saturated aqueous NaHCO₃ solution (3×)and water, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue is purified by flash chromatography on silica gel. Elution withhexanes-EtOAc (70:30) affords Int 2 as a clear oil (62% yield): ¹H NMR(CDCl₃) δ7.4-7.2, 7.0, 6.0, 4.2, 3.8, 3.4, 2.1-1.8, 1.3.

Step C. Preparation oftrans-4-nitro-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int3).

A solution of hit 1 (6.81 g, 34.9 mmol) and Int 2 (7.65 g, 34.9 mmol) inEtOH (70 mL) stirs at rt for 15 h and is then concentrated in vacuo. Theresidue is diluted with ether (100 mL) and saturated aqueous NaHCO₃solution (100 mL). The organic layer is separated and dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product is purified byflash chromatography on silica gel. Elution with hexanes-EtOAc (85:15)affords Int 3 as a clear oil (76% yield): ¹H NMR (CDCl₃) δ7.4-7.3,4.8-4.7, 4.1, 3.8-3.6, 3.3-3.0, 2.7-2.6, 2.4-2.3, 1.2.

Step D. Preparation oftrans-4-amino-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int4).

A mixture of Int 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in EtOH (100 mL)is placed in a Parr bottle and hydrogenated for 4 h under an atmosphereof hydrogen (46 psi) at rt. The mixture is filtered through a pad ofCelite, and the solvent is removed in vacuo to afford Int 4 as a clearoil (100% yield): ¹H NMR (300 MHz, CDCl₃) δ7.3-7.2, 4.1, 3.6, 3.2,3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.

Step E. Preparation oftrans-4-(1,1-dimethylethoxycarbonylamido)-1-(phenylmethyl)-3-pyrrolidineaceticacid ethyl ester (Int 5).

Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) is added to a stirredsolution of Int 4 (2.94 g, 11.2 mmol) in CH₂Cl₂ (30 mL) cooled in an icebath. The reaction is allowed to warm to rt and stirred overnight. Themixture is concentrated in vacuo. The crude product is purified by flashchromatography on silica gel. Elution with hexanes-EtOAc (80:20) affordsInt 5 as a white solid (77% yield): ¹H NMR (300 MHz, CDCl₃) δ7.4-7.2,5.1-4.9, 4.1, 4.0-3.8, 3.6, 3.2-3.0, 2.8-2.6, 2.5-2.4, 2.3-2.1, 1.4,1.3.

Step F. Preparation of trans(tert-butoxycarbonylamino)-4-(2-hydroxyethyl)-1-(N-phenylmethyl)pyrrolidine (Int 6).

LiAlH₄ powder (627 mg, 16.5 mmol) is added in small portions to astirred solution of Int 5 (3.0 g, 8.3 mmol) in anhydrous THF (125 mL) ina −5° C. bath. The mixture is stirred for 20 min in a −5° C. bath, thenquenched by the sequential addition of water (0.6 mL), 15% (w/v) aqueousNaOH (0.6 mL) and water (1.8 mL). Excess anhydrous K₂CO₃ is added, andthe mixture is stirred for 1 h, then filtered. The filtrate isconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel. Elution with EtOAc affords Int 6 as a white solid (94%yield): ¹H NMR (CDCl₃) δ7.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3.7, 3.3-3.2,2.8-2.7, 2.3-2.1, 1.7, 1.5.

Int 6 is a racemic mixture that can be resolved via chromatography usinga Diacel chiral pack AD column. From the two enantiomers thus obtained,the (+)-enantiomer, [α]²⁵D+35 (c 1.0, MeOH), gives rise to thecorresponding enantiomerically pure exo-4-S final compounds, whereas the(−)-enantiomer, [α]²⁵D-34 (c 0.98, MeOH), gives rise to enantiomericallypure exo-4-R final compounds making non-critical changes of the methodsprovided herein.

Step G. Preparation of exo3-(tert-butoxycarbonylamino)-1-azabicyclo[2.2.1]heptane (Int 7).

TEA (8.0 g, 78.9 mml) is added to a stirred solution of Int 6 (2.5 g,7.8 mmol) in CH₂Cl₂ (50 mL), and the reaction is cooled in an ice-waterbath. CH₃SO₂Cl (5.5 g, 47.8 mmol) is then added dropwise, and themixture is stirred for 10 min in an ice-water bath. The resulting yellowmixture is diluted with saturated aqueous NaHCO₃ solution, extractedwith CH₂Cl₂ several times until no product remains in the aqueous layerby TLC. The organic layers are combined, washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue is dissolved in EtOH (85mL) and is heated to reflux for 16 h. The reaction mixture is allowed tocool to rt, transferred to a Parr bottle and treated with 10% Pd/Ccatalyst (1.25 g). The bottle is placed under an atmosphere of hydrogen(53 psi) for 16 h. The mixture is filtered through Celite, and freshcatalyst (10% Pd/C, 1.25 g) is added. Hydrogenolysis continuesovernight. The process is repeated three more times until thehydrogenolysis is complete. The final mixture is filtered through Celiteand concentrated in vacuo. The residue is purified by flashchromatography on silica gel. Elution with CHCl₃—MeOH—NH₄OH (90:9.5:0.5)affords Int 7 as a white solid (46% yield): ¹H NMR (CDCl₃) δ5.6-5.5,3.8-3.7, 3.3-3.2, 2.8-2.7, 2.0-1.8, 1.7-1.5, 1.5.

Step H. Preparation of exo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate).

Para-toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) is added to astirred solution of Int 7 (770 mg, 3.63 mmol) in EtOH (50 mL). Thereaction mixture is heated to reflux for 10 h, followed by cooling tort. The precipitate is collected by vacuum filtration and washed withcold EtOH to give exo-[2.2.1]-3-Amine (as a racemix mixture) as a whitesolid (84% yield): ¹H NMR (CD₃OD) δ7.7, 7.3, 3.9-3.7, 3.7-3.3, 3.2, 2.4,2.3-2.2, 1.9-1.8. The corresponding amines can be obtained by using theresolved Int 6 to give exo-(4R)-[2.2.1]-3-Amine andexo-(4S)-[2.2.1]-3-Amine.

Synthesis of endo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt:

Step I. Preparation of ethyl5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine4-carboxylate (Int 10).

Absolute EtOH (92.0 mL, 1.58 mol) is added to a mechanically stirredsuspension of potassium ethoxide (33.2 g, 395 mmol) in dry toluene(0.470 L). When the mixture is homogeneous, 2-pyrrolidinone (33.6 g, 395mmol) is added, and then a solution of diethyl oxalate (53.1 mL, 390mmol) in toluene (98 mL) is added via an addition funnel. After completeaddition, toluene (118 mL) and EtOH (78 mL) is added sequentially. Themixture is heated to reflux for 18 h. The mixture is cooled to rt andaqueous HCl (150 mL of a 6.0 M solution) is added. The mixture ismechanically stirred for 15 min. The aqueous layer is extracted withCH₂Cl₂, and the combined organic layers are dried over MgSO₄, filteredand concentrated in vacuo to a yellow residue. The residue isrecrystallized from EtOAc to afford Int 10 as a yellow solid (38%yield): ¹H NMR (CDCl₃) δ11.4, 7.4, 4.3, 3.4, 2.6, 1.3.

Step J. Preparation of ethyl cis-3-hydroxy-2-oxopiperidine4-carboxylate(Int 11).

A mixture of Int 10 (15 g, 81 mmol) and 5% rhodium on carbon (2.0 g) inglacial acetic acid is placed under an atmosphere of hydrogen (52 psi).The mixture is shaken for 72 h. The mixture is filtered through Celite,and the filtrate is concentrated in vacuo to afford Int 11 as a whitesolid (98% yield): ¹H NMR (CDCl₃) δ6.3, 4.2, 4.0-3.8, 3.4, 3.3-3.2, 2.2,1.3.

Step K. Preparation of cis-4-(hydroxymethyl)piperidin-3-ol (Int 12).

Int 11 (3.7 g, 19.9 mmol) as a solid is added in small portions to astirred solution of LiAlH₄ in THF (80 mL of a 1.0 M solution) in anice-water bath. The mixture is warmed to rt, and then the reaction isheated to reflux for 48 h. The mixture is cooled in an ice-water bathbefore water (3.0 mL, 170 mmol) is added dropwise, followed by thesequential addition of NaOH (3.0 mL of a 15% (w/v) solution) and water(9.0 mL, 500 mmol). Excess K₂CO₃ is added, and the mixture is stirredvigorously for 15 min. The mixture is filtered, and the filtrate isconcentrated in vacuo to afford Int 12 as a yellow powder (70% yield):¹H NMR (DMSO-d₆) δ4.3, 4.1, 3.7, 3.5-3.2, 2.9-2.7, 2.5-2.3, 1.5, 1.3.

Step L. Preparation of benzylcis-3-hydroxy4-(hydroxymethyl)piperidine-1-carboxylate (Int 13).

N-(benzyloxy carbonyloxy)succinimide (3.04 g, 12.2 mmol) is added to astirred solution of Int 12 (1.6 g, 12.2 mmol) in saturated aqueousNaHCO₃ (15 mL) at rt. The mixture is stirred at rt for 18 h. The organicand aqueous layers are separated. The aqueous layer is extracted withether (3×). The combined organic layers are dried over anhydrous K₂CO₃,filtered and concentrated in vacuo to afford Int 13 as a yellow oil (99%yield): ¹H NMR (CDCl₃) δ7.4-7.3, 5.2, 4.3,4.1, 3.8-3.7, 3.0-2.8, 2.1,1.9-1.7, 1.4.

Step M. Preparation of benzyl cis-3-hydroxy4-[(4-methylphenyl)sulfonyloxymethyl]piperidine-1-carboxylate (Int 14).

Para-toluenesulfonyl chloride (1.0 g, 5.3 mmol) is added to a stirredsolution of Int 13 (3.6 g, 5.3 mmol) in pyridine (10 mL) in a −15° C.bath. The mixture is stirred for 4 h, followed by addition of HCl (4.5mL of a 6.0 M solution). CH₂Cl₂ (5 mL) is added. The organic and aqueouslayers are separated. The aqueous layer is extracted with CH₂Cl₂. Thecombined organic layers are washed with brine, dried over MgSO₄,filtered and concentrated in vacuo to afford Int 14 as a colorless oil(78% yield): ¹H NMR (CDCl₃) δ7.8, 7.4-7.2, 5.1, 4.3-4.2, 4.1, 3.9-3.8,2.9-2.7, 2.4, 1.9, 1.6-1.3.

Step N. Preparation of exo-1-azabicyclo[2.2.1]heptan-3-ol (Int 15).

A mixture of Int 14 (3.6 g, 8.6 mmol) and 10% Pd/C catalyst (500 mg) inEtOH (50 mL) is placed under an atmosphere of hydrogen. The mixture isshaken for 16 h. The mixture is filtered through Celite. Solid NaHCO₃(1.1 g, 13 mmol) is added to the filtrate, and the mixture is heated inan oil bath at 50° C. for 5 h. The solvent is removed in vacuo. Theresidue is dissolved in saturated aqueous K₂CO₃ solution. Continuousextraction of the aqueous layer using a liquid-liquid extractionapparatus (18 h), followed by drying the organic layer over anhydrousK₂CO₃ and removal of the solvent in vacuo affords Int 15 as a whitesolid (91% yield): ¹H NMR δ3.8, 3.0-2.8, 2.6-2.5, 2.4-2.3, 1.7, 1.1.

Step O. Preparation of endo-3-azido-1-azabicyclo[2.2.1]heptane (Int 16).

To a mixture of Int 15 (1.0 g, 8.9 mmol) and triphenyl phosphine (3.0 g,11.5 mmol) in toluene-THF (50 mL, 3:2) in an ice-water bath are addedsequentially a solution of hydrazoic acid in toluene (15 mL of ca. 2 Msolution) and a solution of diethyl azadicarboxylate (1.8 mL, 11.5 mmol)in toluene (20 mL). The mixture is allowed to warm to rt and stir for 18h. The mixture is extracted with aqueous 1.0M HCl solution. The aqueouslayer is extracted with EtOAc, and the combined organic layers arediscarded. The pH of the aqueous layer is adjusted to 9 with 50% aqueousNaOH solution. The aqueous layer is extracted with CH₂Cl₂ (3×), and thecombined organic layers are washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product is purified byflash chromatography on silica gel. Elution with CHCl₃—MeOH—NH₄OH(92:7:1) affords Int 16 as a colorless oil (41% yield): ¹H NMR (CDCl₃)δ4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.

Step P. Preparation of endo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate).

A mixture of Int 16 (250 mg, 1.8 mmol) and 10% Pd/C catalyst (12 mg) inEtOH (10 mL) is placed under an atmosphere of hydrogen (15 psi). Themixture is stirred for 1 h at rt. The mixture is filtered throughCelite, and the filtrate is concentrated in vacuo. The residue isdissolved in EtOH (10 mL) and para-toluenesulfonic acid monohydrate (690mg, 3.7 mmol) is added. The mixture is stirred for 30 min, and theprecipitate is filtered. The precipitate is washed sequentially withcold EtOH and ether. The precipitate is dried in vacuo to affordendo-[2.2.1]-3-Amine as a white solid (85% yield): ¹H NMR (CD₃OD) δ7.7,7.3, 4.2, 3.9, 3.6-3.4, 3.3-3.2, 2.4, 2.3, 2.1.

Preparation of the 3.2.1-Amine:

The exo- and endo-1-azabicyclo[3.2.1]octan-3-amines are prepared from1-azabicyclic[3.2.1]octan-3-one (Thill, B. P., Aaron, H. S., J. Org.Chem., 4376-4380 (1968)) according to the general procedure as discussedin Lewin, A. H., et al., J. Med. Chem., 988-995 (1998).

exo-1-Azabicyclo [3.2.1] octan-3-amine dihydrochloride(exo-[3.2.1]-Amine):

A mixture of 1-azabicyclo[3.2.1]octan-3-one hydrochloride (2.80 g, 17.3mmol), ethanol (25 mL), and hydroxylamine hydrochloride (1.56 g, 22.4mmol) is treated with sodium acetate trihydrate (7.07 g, 51.2 mmol). Themixture is stirred for 3 h and evaporated in vacuo. The residue isdiluted with CH₂Cl₂, treated with charcoal, filtered and evaporated. Theresulting material is taken up in 1-propanol (45 mL) and heated in a100° C. oil bath. The solution is treated with sodium metal (6.4 g inportions). Heating is continued for 3 h and the mixture cooled to rt.Water is added carefully and the organic layer is extracted, dried(MgSO₄), filtered, acidified with MeOH/HCl(g), and evaporated.2-Propanol is added and the resulting solid is filtered and dried invacuo to give exo-[3.2.1]-Amine in 49% yield. MS for C₇H₁₄N₂·(HCl)₂(ESI) (M+H)⁺ m/z=127.

endo-1-Azabicyclo[3.2.1]octan-3-amine dihydrochloride(endo-[3.2.1]-Amine):

A mixture of 1-azabicyclo[3.2.1]octan-3-one hydrochloride (2.80 g, 17.3mmol), ethanol (25 mL), and hydroxylamine hydrochloride (1.56 g, 22.4mmol) is treated with sodium acetate trihydrate (7.07 g, 51.2 mmol). Themixture is stirred for 3 h and evaporated in vacuo. The residue isdiluted with CH₂Cl₂, treated with charcoal, filtered and evaporated. Theresulting oxime (3.1 mmol) is treated with acetic acid (30 mL) andhydrogenated at 50 psi over PtO₂ (50 mg) for 12 h. The mixture is thenfiltered and evaporated. The residue is taken up in a minimal amount ofwater (6 mL) and the pH is adjusted to >12 using solid NaOH. The mixtureis then extracted with ethyl acetate (4×25 mL), dried over MgSO₄,filtered, treated with ethereal HCl, and evaporated to giveendo-[3.2.1]-Amine.

1-Azabicyclo[3.2.1]octan-3-amine:

Preparation of the 3R,5R-[3.2.1J-Amine:

This amine can also be prepared according to the following method:(3S)-1-[(S)-1-Phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid:

According to the literature procedure (Nielsen et al. J. Med. Chem 1990,70-77), a mixture of itaconic acid (123.17 g, 946.7 mmol) and(S)-(−)-α-methyl benzylamine (122.0 mL, 946.4 mmol) are heated (neat) ina 160° C. oil bath for 4 h. Upon cooling, MeOH (˜200 mL) is added andthe resulting solid collected by filtration. The solid is treated withETOH (˜700 mL) and warmed using a steam bath until ˜450 mL solventremained. After cooling to rt, the solid is collected and dried toafford 83.2 g as a crystalline solid: [α]²⁵D=−80 (c 0.97, DMSO). ¹H NMR(400 MHz, DMSO-d₆) δ12.66, 7.20-7.40, 5.23, 3.40-3.55, 3.10-3.25,2.40-2.65, 1.45; MS (EI) m/z 233 (M⁺).(3S)-1-[(S)-1-Phenethyl]-3-(hydroxymethyl)pyrrolidine:

A suspension (3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylicacid (82.30 g, 352.8 mmol) in Et₂O (200 mL) is added in small portionsto a slurry of LiAlH₄ (17.41 g, 458.6 mmol) in Et₂O (700 mL). Themixture begins to reflux during the addition. The addition funnelcontaining the suspension is rinsed with Et₂O (2×50 mL), and the mixtureis heated in a 50° C. oil bath for an additional 2 h and first allowedto cool to rt and then further cooled using an ice bath. The mixture iscarefully treated with H₂O (62 mL). The resulting precipitate isfiltered, rinsed with Et₂O, and discarded. The filtrate is concentratedto a yellow oil. When EtOAc is added to the oil, a solid began to form.Hexane is then added, and the mixture is filtered and the solid is driedto afford 43.3 g. [α]²⁵D=−71 (c 0.94, CHCl₃); ¹H NMR (400 MHz, CDCl₃)δ7.20-7.45, 3.60-3.70, 3.40-3.60, 3.19, 3.05-3.15, 2.35-2.55, 2.25-2.35,1.95-2.10, 1.75-1.90, 1.42; HRMS (FAB) calcd for C₁₃H₁₉NO (MH⁺)206.1545, found 206.1532.(3R)-1-[(S)-1-Phenethyl]-3-(cyanomethyl)pyrrolidine:

A solution of (3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine(42.75 g, 208.23 mmol) in chloroform (350 mL) is heated to reflux underN₂. The solution is treated with a solution of thionyl chloride (41.8mL, 573 mmol) in chloroform (40 mL) dropwise over 45 min. The mixture isstirred for an additional 30 min, is cooled and concentrated. Theresidue is diluted with H₂O (˜200 mL), 1 N NaOH is added until a pH ˜8(pH paper). A small portion (˜50 mL) of sat. NaHCO₃ is added and thebasic mixture is extracted with EtOAc (3×400 mL), washed with brine,dried over MgSO₄, filtered and concentrated to give 46.51 g of(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine: MS (ESI+) m/z224.2 (MH⁺). The chloride (46.35 g, 208.0 mmol) is transferred to aflask, DMSO (200 mL) is added, and the solution is treated with NaCN(17.84 g, 363.9 mmol). The mixture is heated under N₂ in a 100° C. oilbath overnight and is cooled. The brown mixture is poured into H₂O (300mL) and is extracted with EtOAc (1000 mL in portions). The combinedorganic layer is washed with H₂O (6×˜50 mL), brine (˜100 mL), dried(MgSO₄), filtered and concentrated to give 40.61 g of an oil: ¹H NMR(400 MHz, CDCl₃) δ7.20-7.40, 3.26, 2.70-2.85, 2.40-2.60, 2.27,2.10-2.20, 1.50-1.70, 1.41; MS (ESI+) for m/z 215.2 (M+H⁺).(3R)-Methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate:

Acetyl chloride (270 mL, 3.8 mol) is carefully added to a flaskcontaining chilled (0° C.) methanol (1100 mL). After the addition iscomplete, the acidic solution is stirred for 45 min (0° C.) and then(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine (40.50 g, 189.0mmol) in methanol (200 mL) is added. The ice bath is removed and themixture is stirred for 100 h at rt. The resulting suspension isconcentrated. Water (˜600 mL) is added, the mixture stirred for 45 minand then the pH is adjusted (made basic) through the addition of ˜700 mLsat. aq. NaHCO₃. The mixture is extracted with EtOAc (3×300 mL). Thecombined organic layers are washed with brine, dried (MgSO₄), filteredthrough celite and concentrated to give 36.86 g as an oil: ¹H NMR (400MHz, CDCl₃) δ7.20-7.40, 3.69, 3.30-3.40, 2.85-2.95, 2.40-2.70,2.00-2.20, 1.10-1.65; MS (ESI+) m/z 248.2 (M+H⁺).(5R)-1-Azabicyclo [3.2.1]octan-3-one hydrochloride:

A solution of (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate(25.72 g, 104.0 mmol) in THF (265 mL) is cooled under N₂ in aCO₂/acetone bath. Next, ICH₂Cl (22.7 mL, 312.0 mmol) is added, and themixture stirred for 30 min. A solution of 2.0M lithium diisopropylamide(heptane/THF/ethylbenzene, 156 mL, 312 mmol) is added slowly over 30min. The internal temperature reached a maximum of −40° C. during thisaddition. After 1 h, sat. NH₄Cl (100 mL) is added and the mixture isallowed to warm to rt. The organic layer is separated, dried (MgSO₄),filtered and concentrated. The resulting foam is chromatographed (300 gSiO₂, CHCl₃—MeOH—NH₄OH (89:10:1) followed by CHCl₃—MeOH (3:1). Theproduct fractions are pooled and concentrated to afford(5R)-3-oxo-1-[(IS)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride(10.12g) as a foam (MS (ESI+) m/z 230.1 (M+H⁺). This foam (10.1 g, 38mmol) is taken up in MeOH (500 mL), 10% Pd(C) (3.0 g) added and themixture is hydrogenated (45 psi) overnight. The mixture is filtered andre-subjected to the reduction conditions (9.1 g, 10% Pd/C, 50 psi).After 5 h, TLC indicates the consumption of the(5R)-3-oxo-1-[(IS)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride.The mixture is filtered, concentrated and triturated (minimal iPrOH) togive 3.73 g in two crops, as a solid: [α]²⁵D=33 (c 0.97, DMSO); HRMS(FAB) calcd for C₇H, NO (M+H⁺) 126.0919, found 126.0937.(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride:

To a flask containing (5R)-1-azabicyclo[3.2.1]octan-3-one hydrochloride(3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g, 29.4 mmol),and ethanol (130 mL) is added sodium acetate trihydrate (9.23 g, 67.8mmol). The mixture stirred for 3 h and is filtered and concentrated. Theresulting white solid is taken up in n-propanol (100 mL) and sodium(˜13.6 g, 618 mmol) is added in 20-25 portions. The reactionspontaneously begins to reflux, and the reaction is heated in an oilbath (100° C.). The addition is complete in ˜20 min and the mixturesolidifies after ˜40 min. The oil bath is removed and n-propanol (2×25mL) is added dissolving the remaining sodium metal. The mixture iscarefully quenched through the dropwise addition of H₂O (100 mL).Saturated aq. NaCl (20 mL) is added, and the layers are separated. Theorganic layer is dried (MgSO₄), filtered, treated with freshly preparedMeOH/HCl, and concentrated. The resulting solid is triturated with 30 mLEtOH, filtered and dried in vaccuo to afford 3.51 g as a white solid:[α]²⁵D=−3 (c 0.94, DMSO); ¹H NMR (400 MHz, DMSO-d₆) δ3.60-3.80,2.95-3.10, 2.65-2.75, 1.90-2.15, 1.70-1.90; HRMS (FAB) calcd for C₇H₁₄N₂(M+H⁺) 127.1235, found 127.1235.

Preparation of 1-azabicyclo[3.2.2]nonan-3-aminebis(4-methylbenzenesulfonate) ([3.2.2]-Amine)

Preparation of tert-butyl 4-(2-oxopropylidene)piperidine-1-carboxylate(Int 101):

Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) is washed withpentane (3×) and suspended in dry THF (40 mL). The solution is cooled to0° C. before diethyl (2-oxopropyl)phosphonate (9.75 g, 50.2 mmol) isadded dropwise. After complete addition, the solution is warmed to rtand stirred for 30 min. tert-Butyl 4-oxo-1-piperidinecarboxylate (5.0 g,25.1 mmol) is added in portions over 10 min, followed by stirring at rtfor 2 h. A saturated aqueous solution of ammonium chloride is added,followed by dilution with ether. The organic layer is extracted withwater. The organic layer is dried over anhydrous MgSO₄, filtered andconcentrated to a yellow oil. The crude product is purified by flashchromatography on silica gel. Elution with hexanes-ether (60:40) gave4.5 g (75%) of Int 101 as a white solid: ¹H NMR (CDCl₃) δ6.2, 3.5, 3.4,2.9, 2.3, 2.2, 1.5.

Preparation of tert-butyl 4-(2-oxopropyl)piperidine-1-carboxylate (hit102):

A mixture of Int 101 (4.5 g, 19 mmol) and 10% palladium on activatedcarbon (450mg) in EtOH (150 mL) is placed in a Parr bottle andhydrogenated for 5 h at 50 psi. The mixture is filtered through Celite,and the filtrate is concentrated in vacuo to afford 4.3 g (94%) of Int102 as a clear oil: ¹H NMR (CDCl₃) δ4.1, 2.8, 2.4, 2.2, 2.0, 1.7, 1.5,1.1.

Preparation of tert-butyl4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (Int 103):

To a stirred solution lithium hexamethyldisilylamide in THF (20.0 mL,1.0 M) in a −78° C. bath is added chlorotrimethylsilane (11.0 mL, 86.4mmol) dropwise. The mixture is stirred at −78° C. for 20 min, followedby addition of Int 102 (3.21 g, 13.3 mmol) in a solution of THF (50 mL)dropwise. After complete addition, the mixture is stirred at −78° C. for30 min. The mixture is warmed to 0° C. in an ice-water bath andphenyltrimethylammonium tribromide (5.25 g, 14.0 mmol) is added. Themixture is stirred in an ice-bath for 30 min, followed by the additionof water and ether. The aqueous layer is washed with ether, and thecombined organic layers were washed with saturated aqueous sodiumthiosulfate solution. The organic layer is dried over anhydrous MgSO₄,filtered and concentrated in vacuo to afford a yellow oil. The crudeproduct is purified by flash chromatography on silica gel. Elution withhexanes-ether (60:40) gave 2.2 g (52%) of Int 103 as a It. yellow oil:¹H NMR (CDCl₃) δ4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1-2.0, 1.7, 1.5,1.2-1.1.2.

Preparation of 1-bromo-3-piperidin-4-ylacetone trifluoroacetate (Int104):

To a stirred solution of Int 103 (2.2 g, 6.9 mmol) in CH₂Cl₂ (30 mL) inan ice-water bath is added trifluoroacetic acid (10 mL, 130 mmol). Themixture is stirred at 0° C. for 30 min. The volatiles were removed invacuo to afford 2.0 g (87%) of hit 104 as a yellow residue: MS (ESI) forC₈H₁₅BrNO [M+H] m/e 220.

Preparation of 1-azabicyclo[3.2.2]nonan-3-one (Int 105):

To a stirred solution of DIEA (13 mL) in acetoniltrile (680 mL) atreflux temperature is added a solution of Int 104 (2.0 g, 6.0 mmol) inacetonitrile (125 mL) over a 4 h period via syringe pump. The mixture iskept at reflux temperature overnight. The mixture is concentrated invacuo and the remaining residue is partitioned between a saturatedaqueous K₂CO₃ solution and CHCl3—MeOH (90:10). The aqueous layer isextracted with CHCl₃—MeOH (90:10), and the combined organic layers weredried over MgSO₄, filtered and concentrated in vacuo to a brown oil. Thecrude product is purified by flash chromatography on silica gel. Elutionwith CHCl₃—MeOH—NH4OH (95:4.5:0.5) gave 600 mg (72%) of Int 105 as aclear solid: ¹H NMR (CDCl₃) δ3.7, 3.3-3.2, 3.1-3.0, 2.7, 2.3, 2.0-1.8.

To a stirred mixture of Int 105 (330 mg, 2.4 mmol) and sodiumacetate-trihydrate (670 mg, 4.8 mmol) in EtOH (6.0 mL) is addedhydroxylamine-hydrochloride (200 mg, 2.8 mmol). The mixture is stirredat rt for 10 h. The mixture is filtered and the filtrate is concentratedin vacuo to a yellow solid. To a solution of the solid (350 mg, 2.3mmol) in n-propanol (30 mL) at reflux temperature is added sodium metal(2.0 g, 87 mmol) in small portions over 30 min. Heating at reflux iscontinued for 2 h. The solution is cooled to rt and brine is added. Themixture is extracted with n-propanol, and the combined organic layersare concentrated in vacuo. The residue is taken up in CHCl₃ and theremaining solids were filtered. The filtrate is dried over anhydrousMgSO₄, filtered and concentrated in vacuo to a clear solid. To a stirredsolution of the solid (320 mg, 2.3 mmol) in EtOH (4 mL) is addedp-toluenesulfonic acid monohydrate (875 mg, 4.6 mmol). The solution iswarmed in a water bath to 45° C. for 30 min, followed by concentrationof the solvent to afford 710 mg (62%) of [3.2.2]-Amine as a white solid:¹H NMR (CD₃OD) δ7.7, 7.3, 4.1-3.9, 3.6-3.4, 2.6-2.5, 2.4, 2.2-2.1,2.1-2.0, 1.9.

Resolution of Stereoisomers:

The amine can be coupled to form the appropriate amides or thioamides asa racemic mixture. The racemic mixture can then be resolved bychromatography using chiral columns or chiral HPLC, techniques widelyknown in the art, to provide the requisite resolved enantiomers 3(R) and3(S) of said amides or thioamides.

The following examples are provided as examples and are not intended tolimit the scope of this invention to only those provided examples andnamed compounds. Also, the salts made in the examples are only exemplaryand are not intended to limit the invention. Any pharmaceuticallyacceptable salt can be made by one of ordinary skill in the art.Further, the naming of specific stereoisomers is for exemplification andthe lack of naming of specific stereoisomers is for simplification, andneither nomenclature method is intended to limit in anyway the scope ofthe invention. The invention includes the following examples in purestereoisomeric form at all optically active centers or as racemicmixtures.

Furthermore, the examples provided are carried out using a specificamine as indicated in the examples. However, any disclosed amine couldbe used making non-critical changes but starting with the appropriateamine. Therefore, the stereospecificity of the resulting compound is notdrawn and may not be stated. But, the scope of this invention includesthe different stereoisomers as described herein as well as racemicmixtures.

Coupling the Amine with the Requisite Acid:

EXAMPLE 1(i)

Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide.fumarate:

2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO₃ (19.5g, 0.232 mole,1.5 equ), and 150 mL of water are placed in a flask. The flask is placedin an oil bath at 90° C., and after 5 min, 37% aqueous formaldehyde(40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in thefollowing order: 12 mL, 3×8 mL, then 2.2 mL all at 90-min intervals andthen the final 2.3 mL after the reaction stirs for 15 h at 90° C. Thereaction is stirred at 90° C. for another 4 h and then cooled by placingthe flask in an ice bath. The pH of the reaction is then adjusted to 1using 6N HCl. The reaction is stirred for 1.5 h in an ice bath allowingan undesired solid to form. The undesired solid is removed byfiltration, and the filtrate is extracted seven times with EtoAc. Thecombined organic extracts are concentrated in vacuo, toluene is added tothe flask and removed in vacuo to azeotrope water, and then CH₂Cl₂ isadded and removed in vacuo to obtain2-chloro-6-(hydroxymethyl)-3-pyridinol (Cl) as a pale yellow solid (81%yield) sufficiently pure for subsequent reaction. MS (ED) for C₆H₆ClNO₂,m/z: 159 (M)⁺.

C1 (11.6 g, 72.7 mmol) and NaHCO₃ (18.3 g, 218 mmol) are added to 200 mLH₂O. The mixture is stirred until homogeneous, the flask is placed in anice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction isstirred over the weekend at rt. The pH of the mixture is adjusted to 3with 2N NaHSO₄, and the mixture is extracted with 4×50 mL EtOAc. Thecombined organic layer is dried over MgSO₄, is filtered, and thefiltrate is concentrated in vacuo to a yellow solid. The crude solid iswashed with EtOAc to provide2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) as an off-white solid(62% yield), and the filtrate is concentrated to a small volume and ischromatographed over 250 g silica gel (230-400 mesh) eluting with2.5:4.5:4:0.1 EtOAc/CH₂Cl₂/hexane/acetic acid to afford additional pureC2 (12% yield). MS (EI) for C₆H₅ClINO₂, m/z: 285(M)⁺.

C2 (13.9 g, 48.6 mmol) is combined with trimethylsilylacetylene (9.6 mL,68 mmol), bis(triphenylphosphine) palladium dichloride (1.02 g, 1.46mmol) and cuprous iodide (139 mg, 0.73 mmol) in 80 mL CHCl₃/40 mL THFunder N₂. TEA (21 mL, 151 mmol) is added, and the reaction is stirred 3h at rt and is diluted with 200 mL CHCl₃. The mixture is washed with2×150 mL 5% HCl and the combined aqueous layers are extracted with 2×50mL CHCl₃. The combined organic layer is washed with 100 mL 50% saturatedNaCl, is dried over MgSO₄, and concentrated in vacuo to an amber oil.The crude material is chromatographed over 350 g silica gel (230-400mesh), eluting with 35% EtOAc/hexane to afford2-chloro-6-(hydroxymethyl)-4-[(trimethylsilyl)ethynyl]-3-pyridinol (C3)as a golden solid (92% yield). MS (EI) for C₁₁H₁₄ClNO₂Si, m/z: 255(M)⁺.

C3 (7.9 g, 31.2 mmol) and cuprous iodide (297 mg, 1.6 mmol) in 60 mLEtOH/60 mL TEA are added to a flask. The reaction is placed in an oilbath at 70° C. for 3.5 h, is cooled to rt, and concentrated in vacuo.The residue is partitioned between 100 mL 5% HCl and CH₂Cl₂ (4×50 mL).The combined organic layer is dried over MgSO₄, filtered, andconcentrated in vacuo to give 6.5 g of a crude amber solid. The crudematerial is chromatographed over 300 g silica gel (230-400 mesh) elutingwith 30-40% EtOAc/hexane. Two sets of fractions with two differentdesired compounds are identified by TLC/UV. The two compounds elutedseparately. The early-eluting pool of fractions is combined andconcentrated to afford[7-chloro-2-(trimethylsilyl)furo[2,3-c]pyridin-5-yl]methanol (C) as awhite solid (46% yield). The later-eluting pool of fractions is combinedand concentrated to provide (7-chlorofuro[2,3-c]pyridin-5-yl)methanol(C4) as a white solid (27% yield). MS (EI) for C₈H₆ClNO₂, m/z: 183 (M)⁺for C4. HRMS (FAB) calculated for C₁₁H₁₄ClNO₂Si m/z: 255.0482, found255.0481 for C5.

C5 (1.05 g, 4.1 mmol) and 10% Pd/C catalyst (1.05 g) are placed in 20 mLabsolute EtOH. Cyclohexene (4 mL, 40.1 mmol) is added, and the reactionis refluxed for 2.5 h, and then filtered through celite. The filter cakeis washed with 1:1 EtOH/CH₂Cl₂, and the filtrate is concentrated to apale yellow solid. The residue is partitioned between 40 mL saturatedNaHCO₃ and extracted with CH₂Cl₂ (4×20 mL). The combined organic layeris dried over MgSO₄, filtered, and then concentrated in vacuo to a paleoil (1.04 g). The pale oil is chromatographed over 50 g silica gel(230-400 mesh) eluting with 50-70% EtOAc/hexane to afford5-hydroxymethyl-2-trimethylsilyl-furo[2,3-c]pyridine (C14) as a whitesolid (90% yield). MS (EI) for C₁₁H₁₅NO₂Si, m/z: 221(M)⁺.

C14 (770 mg, 3.48 mmol) is dissolved in 10 mL MeOH. 2N NaOH (3 mL, 6mmol) is added, and the reaction is stirred for 1.5 h at rt. Thesolution is concentrated in vacuo to a residue. Water (20 mL) is addedto the residue and extracted with 4×10 mL CH₂Cl₂. The combined organiclayer is dried over anhydrous K₂CO₃, filtered, and concentrated in vacuoto afford furo[2,3-c]pyridin-5-yl methanol (C16) as a white solid (90%yield). Analysis calculated for C₈H₇NO₂:C, 64.42; H, 4.73; N, 9.39.Found: C, 64.60; H, 4.56; N, 9.44.

Oxalyl chloride (685 μL, 7.8 mmol) is dissolved in 30 mL CH₂Cl₂ in a dryflask under N₂. The flask is placed in a dry-ice/acetone bath, DMSO(1.11 mL, 15.6 mmol) in 5 mL CH₂Cl₂ is added drop-wise, and the mixtureis stirred for 20 min. C16 (1.0 g, 6.7 mmol) in 10 mL CH₂Cl₂ is added,and the reaction is stirred 30 min at −78° C. TEA (4.7 mL, 33.5 mmol) isadded, the reaction is allowed to warm to rt, is stirred 1 h, and washedwith 25 mL saturated NaHCO₃. The organic layer is dried over anhydrousK₂CO₃, filtered, and concentrated in vacuo to an orange solid. The crudematerial is chromatographed over 50 g silica gel (230-400 mesh) elutingwith 33% EtOAc/hexane to provide furo[2,3-c]pyridine-5-carbaldehyde(C17) as a white solid (86% yield). MS (EI) for C₈H₅NO₂, m/z: 147 (M)⁺.

C17 (850 mg, 5.8 mmol) is dissolved in 10 mL DMSO. KH₂PO₄ (221 mg, 1.6mmol) in 3 mL H₂O is added and then NaClO₂ (920 mg, 8.2 mmol) in 7 mLH₂O is added, and the reaction is stirred 3 h at rt. The reaction isdiluted with 25 mL water, the pH is adjusted to 10 with 2N NaOH, and themixture is extracted with 3×20 mL ether. The combined ether layer isdiscarded. The pH of the aqueous layer is adjusted to 3.5 with 10%aqueous HCl and is extracted with 13×10 mL 10% MeOH/CH₂Cl₂. TheMeOH/CH₂Cl₂ organic layer is dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo to a pale oil. The residual DMSO is removed undera stream of N₂ at rt to provide a white paste. The paste is dissolved inMeOH and concentrated to dryness. The white solid is washed with etherand dried to afford crude furo[2,3-c]pyridine-5-carboxylic acid (C18)(94% yield). MS (ESI) for C₈H₅NO₃, 162.8 (M−H)⁻.

Step 1a. Preparation of the Carboxamide:

To a stirred solution of furo[2,3-c]pyridine-5-carboxylic acid (C18)(294 mg, 1.80 mmol) in dry THF-DMF (12 mL, 5:1) is added DIEA (956 μL,5.49 mmol), followed by exo-(4S)-[2.2.1]-3-Amine (747 mg, 1.64 mmol).The solution is cooled with an ice bath before HATU (684 mg, 1.80 mmol)is added. The solution is allowed to warm to rt and stir for 16 h. Thesolvent is removed in vacuo, and the remaining residue is partitionedbetween saturated aqueous K₂CO₃ solution and 9:1 CHCl₃—MeOH. The aqueouslayer was extracted with 9:1 CHCl₃—MeOH, and the combined organic layersare washed with brine, dried over MgSO₄, filtered and concentrated invacuo to afford the desired carboxamide as a light yellow solid (420 mg,100%): MS for C₁₄H₁₆N₃O₂ (ESI) m/e 258 (M+H).

Step 1b. Preparation of the Fumarate Salt.

To a stirred solution of the product from Step 1a (200mg, 0.78 mmol) inacetone (5 mL) is added a hot solution of fumaric acid (90 mg, 0.78mmol) in IPA (2 mL). The mixture is stirred for 30 min in a 50° C. waterbath. The solvents are removed in vacuo and the remaining residue isdissolved in acetone (5 mL). The mixture is stirred overnight at rt. Thesolid precipitate is collected by filtration and washed with acetone.The solid is dried in vacuo overnight to give 156 mg (54%) of Example1(i) as a white solid: ¹H NMR (CD₃OD) δ8.9, 8.5, 8.1, 7.1, 6.7, 4.3,3.7, 3.6, 3.4, 3.3, 3.2, 3.1, 2.2, 1.9.

EXAMPLE 1(i-b)

Exo-4(R)—N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide,using exo-(4R)-[2.2.1]-3-Amine: ¹H NMR (400 MHz, MeOH-d₄) δ8.9, 8.5,8.1, 7.1, 6.7, 4.3, 3.7, 3.6, 3.4, 3.3, 3.2, 3.1, 2.2, 1.9.

EXAMPLE 1(i-c)

Exo-(racemic)—N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide,using exo-[2.2.1]-3-Amine.

EXAMPLE 1(i-d)

(+)-N-[endo-1-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamideand

EXAMPLE 1(i-e)

(−)-N-[endo-1-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamide:

To a stirred solution of furo[2,3-c]pyridine-5-carboxylic acid (400 mg,0.877 mmol) in anhydrous DMF (10 mL) are added DIEA (626 μL, 3.59 mmol)and endo-[2.2.1]-3-Amine (175 mg, 0.877 mmol). The mixture is cooled to0° C. in an ice bath, and HATU (333 mg, 0.877 mmol) is added in oneportion. The reaction mixture is allowed to warm to rt and stirovernight. The solvent is removed in vacuo, and the residue ispartitioned between saturated aqueous K₂CO₃ solution and CHCl₃. Theaqueous layer is extracted with CHCl₃ (2×). The combined organic layersare washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo to give 230 mg solid. The racemic mixture is resolved viachromatography using a Chiralcel OJ column. The amides are converted totheir fumarate salt forms as described in Step 1b. The (+)-enantiomer([α]²⁵D 31 (c 0.28, MeOH)) gives rise to Example 1-d, and the(−)-enantiomer ([α]²⁵D −31 (c 0.30, MeOH)) gives rise to Example 1-e.For Example 1-d: ¹H NMR (400 MHz, CD₃OD) δ8.94, 8.46, 8.14, 7.13, 6.71,4.75-4.70, 3.86-3.79, 3.48-3.42, 3.28-3.21, 2.21-2.03.

EXAMPLE 1(i-f)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 1(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 1(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide: Thisexample can be prepared according to the coupling procedures discussedherein.

EXAMPLE 1(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide: Thisexample can be prepared according to the coupling procedures discussedherein.

EXAMPLE 1(v):N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide:Yield from coupling is 70%. HRMS (FAB) calcd for C₁₅H₁₇N₃O₂ (MH⁺)272.1399, found 272.1413. EXAMPLE 1(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)furo[2,3-c]pyridine-5-carboxamide.fumarate:Example 1(vi) is obtained as a white solid: ¹H NMR (CD₃OD) δ8.9, 8.4,8.1, 7.1, 6.7, 4.8-4.7, 3.8, 3.7-3.6, 3.5-3.3, 2.4, 2.2-2.0.

EXAMPLE 2(i)

N-[(exo-1-azabicyclo[2.2.1]hept-3-yl]furo[3,2-c]pyridine-6-carboxamide:

3-Bromofuran (8.99 mL, 100.0 mmol) is dissolved in DMF (8.5 mL), cooledto 0° C., treated dropwise with POCl₃ (9.79 mL, 105.0 mmol), stirred for1 h at RT and then heated to 80° C. for 2 h. The mixture is cooled toRT, poured over ice (1 kg) and neutralized to pH 9 with solid K₂CO₃. Themixture is stirred for 1 h, extracted with Et₂O (3×500 mL), dried overK₂CO₃ and concentrated to a dark brown oil. The crude material ischromatographed over 600 g slurry-packed silica gel, eluting with 6%EtOAc/hexane (4 L), 8% EtOAc/hexane (2 L), 10% EtOAc/hexane (1 L), andfinally 20% EtOAc/hexane. The appropriate fractions are combined andconcentrated in vacuo to afford 14.22 g (81%) of 3-bromo-2-furaldehydeas a yellow oil. MS (EI) m/z: 174 (M⁺).

3-Bromo-2-furaldehyde (14.22 g, 81.3 mmol) is combined with ethyleneglycol (6.55 mL, 117.4 mmol) and para-toluene sulfonic acid monohydrate(772 mg, 4.06 mmol) in benzene (200 mL) and heated to reflux with aDean-Stark trap for 5 h. Additional ethylene glycol (1.64 mL, 29.41mmol) and benzene (150 mL) are added and the solution is heated for anadditional 2 h. The mixture is cooled to RT, treated with saturatedNaHCO₃ and stirred for 0.5 h. The layers are separated and the organicsare dried over Na₂SO₄ and concentrated to a brown oil (18.8 g). Thecrude material is chromatographed over 700 g slurry-packed silica gel,eluting with 15% EtOAc/hexane. The appropriate fractions are combinedand concentrated in vacuo to afford 16.45 g (92%) of2-(3-bromo-2-furyl)-1,3-dioxolane as a yellow-orange oil. MS (EI) m/z:218 (M⁺).

2-(3-Bromo-2-furyl)-1,3-dioxolane (438 mg, 2.0 mmol) is dissolved inEt₂O (5 mL) in a dry flask under nitrogen, cooled to −78° C., treateddropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 h.DMF (178 μL, 2.3 mmol) in Et₂O (2 mL) is added dropwise, the mixturestirred for 4 h at −78° C., then treated with oxalic acid dihydrate (504mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed andthe mixture allowed to warm to RT over 1 h. The mixture is diluted withwater (20 mL) and EtOAc (20 mL), the layers are separated and theaqueous layer extracted with EtOAc (1×20 mL). The organics are driedover Na₂SO₄ and concentrated to a yellow oil. The crude material ischromatographed over 12 g slurry-packed silica gel, eluting with 15%EtOAc/hexane. The appropriate fractions are combined and concentrated invacuo to afford 228 mg (68%) of 2-(1,3-dioxolan-2-yl)-3-furaldehyde as apale yellow oil. MS (EI) m/z: 168 (M⁺).

2-(1,3-Dioxolan-2-yl)-3-furaldehyde (2.91 g, 17.31 mmol) is combinedwith formic acid (17 mL, 451 mmol) and water (4.25 mL) and stirred at RTfor 18 h. The mixture is slowly transferred into a solution of NaHCO₃(45 g, 541 mmol) in water (600 mL), then strirred for 0.5 h. EtOAc (200mL) is added, the layers separated and the aqueous layer extracted withEtOAc (2×200 mL). The combined organics are dried over Na₂SO₄ andconcentrated to a yellow oil (3.28 g). The crude material ischromatographed over 90 g slurry-packed silica gel, eluting with 20%EtOAc/hexane. The appropriate fractions are combined and concentrated toafford 2.45 g of furan-2,3-dicarbaldehyde slightly contaminated withethylene glycol diformate as a yellow oil. ¹H NMR (CDCl₃): δ7.00 (d, J=2Hz, 1 H), 7.67 (d, J=2 Hz, 1 H), 10.07 (s, 1 H), 10.49 (s, 1 H) ppm.

Methyl (acetylamino)(dimethoxyphosphoryl)acetate (2.34 g, 9.8 mmol) isdissolved in CHCl₃ (40 mL), treated with DBU (1.46 mL, 9.8 mmol),stirred for 5 min then added dropwise to a 0° C. solution offuran-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in CHCl₃ (80 mL). Themixture is stirred for 2.5 h as the cooling bath expires then 5.5 h atRT and finally 24 h at 50° C. The mixture is concentrated in vacuo to ayellow oily-solid (6.66 g). The crude material is chromatographed over astandard 100 g slurry-packed silica gel, eluting with 65% EtOAc/hexane.The appropriate fractions are combined and concentrated in vacuo toafford 1.30 g (82%) of methyl furo[3,2-c]pyridine-6-carboxylate as ayellow solid. MS (EI) m/z: 177 (M⁺).

Methyl furo[3,2-c]pyridine-6-carboxylate (1.55 g, 8.74 mmol) isdissolved in MeOH (30 mL) and H₂O (15 mL), treated with 3 N NaOH (6.4mL) and stirred at RT for 7 h. The mixture is concentrated to dryness,dissolved in H₂O (10 mL) and acidified to pH 2 with concentrated HCl.The solution is concentrated to dryness, suspended in a smaller amountof water (7 mL) and the resulting solid collected via filtration (lotA). The filtrate is concentrated, triturated with water (3 mL) and theresulting solid collected via filtration (lot B). The filtrate from lotB is concentrated and carried on without further purification as anacid/salt mixture (lot C). Both lots A and B are dried in a vacuum ovenat 50° C. for 18 h to afford 690 mg (48%) for lot A and 591 mg (42%) forlot B of furo[3,2-c]pyridine-6-carboxylic acid as yellow solids. MS (CI)m/z: 164 (M+H⁺).

Examples 2(i), 2(i-a), 2(ii), 2(iii), 2(iv), and 2(vi) can be preparedaccording to the coupling procedures described herein, makingnon-critical changes.

EXAMPLE 2(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)furo[3,2-c]pyridine-6-carboxamide.

EXAMPLE 2(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide.

EXAMPLE 2(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide.

EXAMPLE 2(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide.

EXAMPLE 2(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide:Yield for coupling is 94%. ¹H NMR (400 MHz, CD₃OD) δ9.30, 8.75-8.80,8.35-8.45, 7.35-7.45, 4.65-4.80, 3.25-3.80, 2.85-2.95, 2.30-2.45,2.10-2.25, 1.95-2.10.

EXAMPLE 2(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)furo[3,2-c]pyridine-6-carboxamide.

EXAMPLE 3(i)

N-(1-azabicyclo[2.2.1]-hept-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide:

Oxalyl chloride (3.1 mL, 35 mmol) is dissolved in 200 mL CH₂Cl₂ in adried flask under N₂. The flask is placed in a dry-ice/acetone bath at−78° C., DMSO (4.95 mL, 70 mmol) in 10 mL CH₂Cl₂ is added drop-wise, andthe mixture is stirred for 20 min.(7-Chlorofuro[2,3-c]pyridin-5-yl)methanol (C4) (5.5 g, 30 mmol) in 10 mLCH₂Cl₂ is added, and the reaction is stirred 30 min at −78° C. TEA (21.3mL, 153 mmol) is then added. The reaction is stirred 30 min in thedry-ice/acetone bath, an ice bath replaces the dry-ice/acetone bath, andthe reaction is stirred 1 h and is washed with 100 mL 1:1 saturatedNaCl/NaHCO₃. The organic layer is dried over anhydrous K₂CO₃, filtered,and concentrated in vacuo to afford7-chlorofuro[2,3-c]pyridine-5-carbaldehyde (C6) as a pale yellow solid(97% yield). MS (EI) for C₈H₄ClNO₂ m/z: 181 (M)⁺.

C6 (3.0 g, 16.5 mmol) is dissolved in 40 mL DMSO. KH₂PO₄ (561 mg, 4.1mmol) in 6.5 mL H₂O is added and then NaClO₂ (2.6 g, 23.1 mmol) in 24 mLH₂O is added, and the reaction is stirred overnight at rt. The reactionis diluted with 200 mL H₂O, the pH is adjusted to 9 with 2N NaOH, andany remaining aldehyde is extracted into 3×50 mL ether. The pH of theaqueous layer is adjusted to 3 with 10% aqueous HCl and is extractedwith 4×50 mL EtOAc. The combined organic layer is dried over MgSO₄,filtered, and concentrated in vacuo to a white solid. The solid iswashed with ether and dried to afford7-chlorofuro[2,3-c]pyridine-5-carboxylic acid (C7) (55% yield). MS (CI)for C₈H₄ClNO₃, m/z: 198 (M+H).

C7 (980 mg, 4.98 mmol) is dissolved in 75 mL MeOH containing 500 mg 20%palladium hydroxide on carbon in a 250 mL Parr shaker bottle. Thereaction mixture is hydrogenated at 20 PSI for 24 h. The catalyst isremoved by filtration and the filtrate is concentrated in vacuo to awhite solid. The solid is dissolved in MeOH and is loaded onto 20 mLDowex 50W-X2 ion exchange resin (hydrogen form) which had been prewashedwith MeOH. The column is eluted with 50 mL MeOH followed by 150 mL 5%TEA in MeOH to afford 2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acid(C8) (74% yield). HRMS (FAB) calculated for C₈H₇NO₃+H: 166.0504, found166.0498 (M+H).

Example 3(i-a) can be prepared according to the coupling proceduresdiscussed herein using C8.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 3(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 3(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 3(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 3(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 3(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 3(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE b 4(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide:

Example 4(i) can be obtained by coupling either the exo-[2.2.1]-3-Amineor endo-[2.2.1]-3-Amine with 7-chlorofuro[2,3-c]pyridine-5-carboxylicacid (C7).

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 4(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 4(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 4(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 4(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 4(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 5(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide:

2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (2) (6.3 g, 22 mmol) isdissolved in 30 mL DMF in a dry flask under N₂. The flask is placed inan ice bath, and 60% sodium hydride in mineral oil (880 mg, 22 mmol) isadded. The reaction is stirred 30 min while the flask is kept in an icebath. The ice bath is removed for 30 min and then the flask is placedback into the ice bath to cool the reaction. 3-Bromo-2-methylpropene(23.1 mmol) is added, and the reaction is stirred overnight at rt. Thereaction is diluted with 150 mL EtOAc and is washed with 4×50 mL 50%saturated 1:1 NaCl/NaHCO₃. The organic layer is dried over anhydrousNa₂SO₄, filtered, and then concentrated in vacuo to a pale oil which iscrystallized from hexanes to afford(6-chloro-4-iodo-5-[(2-methyl-2-propenyl)oxy]-2-pyridinyl)methanol (C19)(86% yield). HRMS (FAB) calculated for C₁₀H₁₁ClINO₂+H: 339.9603, found339.9604 (M+H).

C19 (6.3 g, 18.9 mmol), sodium formate (1.49 g, 21.8 mmol), TEA (8 mL,57.2 mmol), palladium acetate (202 mg, 0.9 mmol) and tetra(n-butyl)ammonium chloride (5.25 g, 18.9 mmol) are added to 30 mL DMF ina dry flask under N₂. The reaction is warmed to 60° C. for 5 h, ispoured into 150 mL EtOAc, and is washed with 4×50 mL 50% saturated 1:1NaCl/NaHCO₃. The organic layer is dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo to a pale oil. The crude material ischromatographed over 40 g silica gel (Biotage), eluting with 30%EtOAc/hexane to afford(7-chloro-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)methanol (C20)(54% yield). MS (EI) for C₁₀H₁₂ClNO₂, m/z: 213 (M)⁺.

C20 (2.11 g, 9.9 mmol) and 600 mg 10% Pd/C catalyst are placed in 30 mLEtOH in a 250 mL Parr shaker bottle. 2N NaOH (5 mL, 10 mmol) is thenadded and the mixture is hydrogenated at 20 PSI for 2.5 h. The catalystis removed by filtration, and the filtrate is concentrated in vacuo toan aqueous residue. Saturated NaHCO₃ (20 mL) is added to the residue andextracted with 4×20 mL CH₂Cl₂. The combined organic layer is dried overanhydrous K₂CO₃, filtered, and concentrated in vacuo to afford(3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)methanol (C21) (92%yield). MS (EI) for C₁₀H₁₃NO₂, m/z: 179 (M)⁺.

Oxalyl chloride (869 μL, 9.9 mmol) is dissolved in 50 mL CH₂Cl₂ in a dryflask under N₂. The flask is placed in a dry-ice/acetone bath at −78°C., DMSO (1.41 mL, 19.8 mmol) in 5 mL CH₂Cl₂ is added drop-wise, and themixture is stirred for 20 min. C21 (1.53 g, 8.5 mmol) in 5 mL CH₂Cl₂ isthen added, and the reaction is stirred 30 min at −78° C. TEA (5.9 mL,42.5 mmol) is added and the reaction is stirred 20 min at −78° C. Thedry-ice/acetone bath is removed, the reaction is stirred 1 h, and thereaction is washed with 25 mL saturated NaHCO₃. The organic layer isdried over anhydrous K₂CO₃, filtered, and then concentrated in vacuo toan orange solid. The crude material is chromatographed over 40 g silicagel (Biotage) eluting with 25% EtOAc/hexane to afford3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carbaldehyde (C22) (92%yield). MS (EI) for C₁₀H₁₁NO₂, m/z: 177 (M)⁺.

C22 (1.35 g, 7.62 mmol) is dissolved in 40 mL THF, 20 mL t-butanol, and20 mL H₂O. KH₂PO₄ (3.11 g, 22.9 mmol) and NaClO₂ (2.58 g, 22.9 mmol) areadded, and the reaction is stirred over the weekend at rt. The reactionis concentrated in vacuo to a residue. The residue is partitionedbetween 20 mL water and CH₂Cl₂ (2×50 mL). The combined organic layer isdried over anhydrous Na₂SO₄, filtered, and then concentrated in vacuo toafford crude 3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylicacid (C23) (99% yield). HRMS (FAB) calculated for C₁₀H₁₁NO₃+H: 194.0817,found 194.0808 (M+H).

Example 5(i) can be obtained by coupling C23 with either theexo-[2.2.1]-3-Amine or the endo-[2.2.1]-3-Amine using the couplingprocedures discussed herein.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 5(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 5(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 5(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 5(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 5(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 6(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide:

2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) (4.6 g, 16 mmol),propargyl trimethylsilane (2 g, 17.8 mmol), bis(triphenylphosphine)palladium dichloride (156 mg, 0.21 mmol), cuprous iodide (122 mg, 0.64mmol), and piperidine (3.52 mL, 26.6 mmol) are added to 25 mL DMF in adry flask under N₂. The mixture is warmed to 45° C. for 7 h, is stirredovernight at rt, and is diluted with 150 mL EtOAc. The mixture is washedwith 4×50 mL 50% saturated 1:1 NaCl/NaHCO₃. The organic layer is driedover anhydrous Na₂SO₄, filtered, and then concentrated in vacuo to anamber oil. The crude material is chromatographed over 40 g silica gel(230-400 mesh) eluting with 35% EtOAc/hexane to afford(7-chloro-2-methylfuro[2,3-c]pyridin-5-yl)methanol (C24) (44% yield). MS(CI) for C₉H₈ClNO₂, m/z: 198 (M+H).

C24 (2.0 g, 10.8 mmol) is added to 500 mg 10% Pd/C catalyst in 25 mLEtOH in a 250 mL Parr shaker bottle. 2N NaOH (6 mL, 12 mmol) is added,and the reaction is hydrogenated at 20 PSI for 6 h. The catalyst isremoved by filtration, and the filtrate is concentrated in vacuo to anaqueous residue. The residue is partitioned between 50 mL 50% saturatedNaCl and 30 mL CH₂Cl₂. The organic layer is dried over anhydrous K₂CO₃,filtered, and then concentrated in vacuo to afford(2-methylfuro[2,3-c]pyridin-5-yl)methanol (C25) (77% yield). MS (CI) forC₉H₉NO₂, m/z: 164 (M+H).

Oxalyl chloride (784 μL, 8.9 mmol) is dissolved in 25 mL CH₂Cl₂ in a dryflask under N₂. The flask is placed in a dry-ice/acetone bath at −78°C., and DMSO (1.26 mL, 17.8 mmol) in 5 mL CH₂Cl₂ is added. The mixtureis stirred for 20 min and C25 (1.53 g, 8.5 mmol) in 5 mL CH₂Cl₂ isadded. The reaction is stirred 1 h, TEA (5.9 mL, 42.5 mmol) is added,and the reaction is stirred 30 min at −78° C. The flask is placed in anice bath, and the reaction is stirred 1 h. The reaction is washed with50 mL saturated NaHCO₃. The organic layer is dried over anhydrous K₂CO₃,filtered, and then concentrated in vacuo to a tan solid. The crudematerial is chromatographed over 40 g silica gel (Biotage) eluting with25% EtOAc/hexane to afford 2-methylfuro[2,3-c]pyridine-5-carbaldehyde(C26) (99% yield). MS (EI) for C₉H₇NO₂, m/z: 161 (M)⁺.

C26 (1.15 g, 7.1 mmol) is dissolved in 40 mL THF, 20 mL t-butanol, and20 mL H₂O. 2-Methyl-2-butene (6.5 mL, 57.4 mmol) is added, and thenKH₂PO₄ (3.11 g, 22.9 mmol) and NaClO₂ (2.58 g, 22.9 mmol) are added. Thereaction is stirred 6 h at rt. The reaction is concentrated in vacuo.Water (20 ml) is added to the residue, a white solid remained. The whitesolid is collected, washed with water and then with ether, and is driedto afford 2-methylfuro[2,3-c]pyridine-5-carboxylic acid (C27) (70%yield). MS (EI) for C₉H₇NO₃, m/z: 177 (M)⁺.

Example 6(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C27.

The examples can be prepared according to the coupling proceduresdiscussed herein:

EXAMPLE 6(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 6(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 6(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 6(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 6(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 7(i)

Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide.furmate:

2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (2) (7.14 g, 25.0 mmol) isdissolved in DMF (50 mL) in a dry flask under N₂, sodium hydride (60%dispersion in mineral oil) (1.0 g, 25.0 mmol) is added, and the reactionis stirred for 1 h at rt. Allyl bromide (2.38 mL, 27.5 mmol) is added,and the reaction mixture is stirred 48 h at rt. The mixture is dilutedwith EtOAc (50 mL) and washed 4×25 mL of a 50% saturated solution of 1:1NaCl/NaHCO₃. The organic layer is dried over MgSO₄, filtered andconcentrated in vacuo to a white solid. The solid is washed with hexaneand dried to afford3-(allyloxy)-2-chloro-6-(hydroxymethyl)-4-iodopyridine (C50) as a whitesolid (68% yield). MS (EI) for C₉H₉ClINO₂, m/z: 325 (M)⁺.

C50 (5.51 g, 16.9 mmol) is suspended in benzene (30 mL) in a dry flaskunder N₂. Azo(bis)isobutyryl nitrile (289 mg, 1.8 mmol) is added, themixture is rapidly heated to reflux, and tributyltin hydride (4.91 mL,18.2 mmol) in benzene (10 mL) is added. The solution is refluxed for 1.5h, allowed to cool to rt and concentrated in vacuo. The resultingresidue is chromatographed over 125 g slurry-packed silica gel, elutingwith a gradient of EtOAc/hexane (20%-60%) to afford(7-chloro-3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)methanol (C5 1) asa white solid (89% yield). MS (ESI) for C₉H₁₀ClNO₂+H, m/z: 200.1 (M+H).

C51 (3.00 g, 15.0 mmol) is added to 20% palladium hydroxide on carbon(800 mg) and 2N NaOH (9.2 mL, 18.2 mmol) in a Parr shaker bottle. Themixture is hydrogenated at 20 PSI for 3 h, is filtered through celiteand concentrated in vacuo to a residue. The resulting residue ispartitioned between H₂O (50 mL) and CH₂Cl₂ (4×30 mL). The combinedorganic layer is dried over MgSO₄, filtered, and concentrated to acolorless oil which solidified upon standing to afford 2.50 g (greaterthan 100% yield) of(3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)methanol (C52) as a whitecrystalline solid. MS (EI) for C₉H₁₁NO₂, m/z: 165 (M)⁺.

C52 (2.48 g, 15.03 mmol) is dissolved in pyridine (15 mL), and aceticanhydride (4.18 mL, 45.09 mmol) is added and stirred for 16 h at rtunder N₂. The reaction is concentrated in vacuo, and the residue isdiluted with EtOAc (75 mL), washed with 50% saturated NaHCO₃ (4×30 mL),and dried over MgSO₄. The organic layer is filtered and concentrated invacuo to afford (3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)methylacetate (C53) as a colorless oil (92% yield). MS (EI) for C₁₁H₁₃NO₃,m/z: 207 (M)⁺.

C53 (2.85 g, 13.8 mmol) is dissolved in dioxane (100 mL),2,3,5,6-tertachlorobenzoquinone (3.72 g, 15.1 mmol) is added, and thereaction is heated to reflux for 17 h. The reaction is concentrated invacuo. The resulting brown solid is washed with 1:1 EtOAc/ether (50 mL),and the insoluble material filtered off. The filtrate is concentrated toa brown solid, dissolved in MeOH (50 mL), treated with 2N NaOH (16 mL,32 mmol), and stirred at rt for 1 h. The mixture is concentrated todryness, dissolved in IN NaOH (75 mL), and extracted with CH₂Cl₂ (4×50mL). The combined organic layer is dried over K₂CO₃, filtered, andconcentrated to a white solid (2.0 g). The crude material is adsorbedonto silica gel (4 g) and chromatographed over a standard 40 g Biotagecolumn, eluting with 90% EtOAc/hexane to afford(3-methylfuro[2,3-c]pyridin-5-yl)methanol (C54) as a white solid (84%yield). MS (ED) for C₉H₉NO₂, m/z: 163 (M)⁺.

Oxalyl chloride (1.16 mL, 13.2 mmol) is added to CH₂Cl₂(30 mL) in a dryflask under N₂ and in a dry-ice/acetone bath at −78° C. DMSO (18.80 mL,26.5 mmol) is slowly added. The solution is stirred for 20 min, and C54(1.88 g, 11.5 mmol) is added. The mixture is stirred for 1 h at −78° C.,then 30 min at 0-5° C. The material is washed with saturated NaHCO₃ (75mL), dried over K₂CO₃, filtered, and concentrated in vacuo to a yellowsolid (3.23 g). The crude material is adsorbed onto silica gel (6 g) andchromatographed over a standard 40 g Biotage column, eluting with 25%EtOAc/hexane to afford 3-methylfuro[2,3-c]pyridine-5-carbaldehyde (C55)as a white solid (72% yield). MS (EI) for C₉H₇NO₂, m/z: 161 (M)⁺.

C55 (1.33 g, 8.28 mmol) is dissolved in THF (50 mL), tert-butylalcohol(25 mL) and H₂O (25 mL), under N₂, and NaClO₂ (2.81 g, 24.84 mmol) andKH₂PO₄ (2.25 g, 16.56 mmol) are added. The reaction mixture is stirredovernight at rt, concentrated to dryness, dissolved in 50% saturatedbrine (60 mL) and extracted with ether (3×). TLC of extracts indicatesacid as well as residual aldehyde, so the organic and aqueous layers arecombined and basified to pH 10 with NH₄OH. The layers are separated andthe residual aldehyde extracted with additional ether. The aqueous layeris acidified to pH 3 with concentrated HCl, then extracted with CH₂Cl₂(4×). Large amounts of acid remained in the aqueous layer, so theaqueous layer is concentrated to dryness. The solid is triturated withCHCl₃ (4×), and then 10% MeOH/CH₂Cl₂ (4×) to extract much of the acidinto the supernatant. The combined organic layer is dried over Na₂SO₄,filtered, and concentrated to a tan solid (1.69 g, greater than 100%isolated yield). The solid is diluted with CHCl₃ and is heated to refluxfor 3 h. The flask is removed from heat, allowed to cool slightly, thenfiltered. The filtrate is concentrated to a tan solid (1.02 g). Thesolid is triturated with ether, filtered and dried to afford3-methylfuro[2,3-c]pyridine-5-carboxylic acid (C56) as a light tan solid(51% yield). MS (CD) for C₉H₇NO₃, m/z: 178 (M+H).

EXAMPLE 7(i) is obtained by coupling exo-(4S)-[2.2.1]-3-Amine with C56,followed by fumarate salt formation as outlined in Steps 1a and 1b,respectively, to afford Example 7(i) in 77% yield. MS for C₁₅H₁₈N₃O₂(ESI) m/e 272 (M+H).

EXAMPLE 7(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 7(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 7(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 7(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 7(v)

(exo)-N-[1-Azabicyclo[3.2.1]oct-3-yl]-3-methylfuro[2,3-c]pyridine-5-carboxamidedihydrochloride.

A mixture of exo-[3.2.1]-Amine (0.199 g, 1.00 mmol), C56 (0.177 g, 1.00mmol), THF (15 mL), DIEA (0.53 mL, 3.02 mmol), and DMF (4 mL) is cooledin an ice bath and treated with HATU (0.380 g, 1.00 mmol). The mixturewarmed to ambient temperature and is evaporated. The residue is dilutedwith CHCl₃ and washed with aqueous NaOH (1N). The organic layer is dried(MgSO₄), filtered, evaporated, and the resulting oil purified by flashcolumn chromatography (1:7:90; conc. NH₄OH—MeOH—CHCl₃). Thebis-hydrocloride salt is formed and triturated with 2-propanol/acetoneto yield the desired product (0.110 g, 30%). MS for C₁₆H₁₉N₃O₂ +H (ESI)(M+H)⁺ m/z=286.

EXAMPLE 8(i)

Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide.furmate:

Starting with 1-chloro-2-butene and2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2), the corresponding3-ethylfuro[2,3-c]pyridine-5-carboxylic acid (C60) was prepared. HRMS(FAB) calculated for C₁₀H₉NO₃+H: 192.0661, found 192.0659 (M+H). Example8 is obtained by coupling exo-4(S)-[2.2.1]-3-Amine with C60 followed byfumarate salt formation as described in Steps 1a and 1b, respectively,to give Example 8(i) in 87% yield. MS for C₁₆H₂₀N₃O₂ (ESI) m/e 286(M+H).

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 8(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 8(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 8(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 8(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 8(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 10(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-furo[2,3-b]pyridine-2-carboxamide:

Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 minutes) toa slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL)under N₂ with the flask being in an ice bath. The mixture is allowed towarm to rt, is stirred for 30 min, and ethyl 2-chloronicotinate (27.84g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 minutes.The reaction is warmed to 65° C. for 15 h in an oil bath. The mixture isconcentrated to dryness, the residue is dissolved in H₂O (500 mL),washed with hexane (500 mL), acidified to pH 3 with 5% HCl, andextracted with CHCl₃ (4×400 mL). The combined organic layer is driedover MgSO₄, filtered, and concentrated to a yellow solid. The solid issuspended in ether (200 mL) and heated on a steam bath untilconcentrated to a volume of 40 mL. The material is allowed tocrystallize overnight, then filtered to afford ethyl3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (C40) as a pale orange solid(41% yield). Additional material is obtained by concentrating thefiltrate. Recrystallization in ether a second time afforded (C40) as apale yellow solid (7.3% yield). MS (EI) for C₁₀H₉NO₄, m/z: 207 (M)⁺.

C40 (207 mg, 1.0 mmol) is added to TEA (139 μL, 1.0 mmol) in CH₂Cl₂ (5mL) at rt and 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine(393 mg, 1.0 mmol) is added. The solution is stirred for 1 h at rt,diluted with EtOAc (25 mL) and washed with 50% saturated brine (2×15mL). The organic layer is dried over Na₂SO₄, filtered, and concentratedto a yellow oil which solidified upon standing. The crude material isadsorbed onto silica gel (1.2 g) and chromatographed over 25 gslurry-packed silica gel, eluting with 20% EtOAc/hexane to afford ethyl3-([(trifluoromethyl)sulfonyl]oxy)furo[2,3-b]pyridine-2-carboxylate(C41) as a white crystalline solid (98% yield). Analysis calculated forC₁₁H₈F₃NO₆S: C, 38.94; H, 2.38; N, 4.13, found: C, 38.84; H, 2.29; N,4.11.

C41 (1.36 g, 4.0 mmol) is added to 10% Pd/C catalyst (68 mg) and NaHCO₃(336 mg, 4.0 mmol) in EtOH (100 mL)/H₂O (5 mL) in a 250 mL Parr shakerbottle. The mixture is hydrogenated at 10 PSI for 5 h, filtered andconcentrated to a residue. The residue is partitioned between 50%saturated NaHCO₃ (80 mL) and EtOAc (80 mL). The organic layer is driedover Na₂SO₄, filtered, and concentrated in vacuo to a colorless oilwhich solidified upon standing (793 mg). The crude material ischromatographed over 40 g slurry-packed silica gel, eluting with 25%EtOAc/hexane to afford ethyl furo[2,3-b]pyridine-2-carboxylate (C42) asa white solid (90% yield). MS (EI) for C₁₀H₉NO₃, m/z: 191 (M)⁺.

C42 (758 mg, 3.96 mmol) is dissolved in MeOH (20 mL) and lithiumhydroxide monohydrate (366 mg, 8.7 mmol) in 6mL H₂O is added under N₂.The reaction is stirred at rt for 2 h, concentrated to near-dryness,diluted with H₂O (5 mL) and acidified to pH 3 with 10% HCl. Theresulting solid is collected by filtration, washed with additional waterand dried to afford furo[2,3-b]pyridine-2-carboxylic acid (C43) as awhite solid (97% yield). MS (EI) for C₈H₅NO₃, m/z: 163 (M)⁺.

Example 10(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C43.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 10(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-furo[2,3-b]pyridine-2-carboxamide.Example 10(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-furo[2,3-b]pyridine-2-carboxamide.

EXAMPLE 10(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-furo[2,3-b]pyridine-2-carboxamide.

EXAMPLE 10(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-furo[2,3-b]pyridine-2-carboxamide.

EXAMPLE 10(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-furo[2,3-b]pyridine-2-carboxamide.

EXAMPLE 10(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-furo[2,3-b]pyridine-2-carboxamide.

EXAMPLE 11(i)

Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide.fumarate:

Using the method used to make the acid for Example 7(i) withnon-critical changes 3-isopropylfuro[2,3-c]pyridine-5-carboxylic acid(C70) is made starting with 1-chloro-3-methyl-2-butene and2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridino (C2). HRMS (FAB) calculatedfor C₁₁H₁₁NO₃+H: 206.0817, found 206.0817 (M+H)⁺.

Example 11(i) is obtained by coupling exo-(4S)-[2.2.1]-3-Amine with C70,followed by fumarate salt formation as outlined in Steps 1a and 1b,respectively, to give Example 11(i) in 89% yield. MS for C₁₇H₂₂N₃O₂(ESI) m/e: 300 (M+H).

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 11(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 11(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 11 (iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 11 (iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 11(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 12(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide:

Example 12(i) can be obtained by adding Example 4(i) (0.72 mmol) andsodium thiomethoxide (0.79 mmol) to DMF (3 mL) and stirring untilExample 4(i) is not present by TLC. The reaction mixture can then bediluted with MeOH and loaded onto a column of AG 50W-X2 resin (hydrogenform), rinsing with MeOH, and eluting the product with approximately 5%TEA/MeOH solution onto a column of AMBERJET 4400 OH resin. The crudematerial can be further purified by chromatography over slurry-packedsilica gel, eluting with approximately 0.5% NH₄OH/8% MeOH/CH₂Cl₂.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 12(-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 12(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 12(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 12(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 12(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5.-carboxamide.

EXAMPLE 13(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-2-carboxamide:

THF (200 mL) in a dry flask under N₂ is chilled by placing the flask ina dry-ice/acetone bath at −78° C. Butyllithium (125 mL, 200 mmol) isadded drop-wise, followed by the drop-wise addition of iodobenzene(11.19 mL, 100 mmol) in THF (10 mL). The solution is allowed to stir for30 min at −78° C. Diisopropylamine (0.70 mL, 5 mmol) in THF (3 mL) and2-chloropyridine (9.46 mL, 100 mmol) in THF (30 mL) are addedsuccessively in a drop-wise manner, and the solution is stirred for 1 hat −40° C. Formyl piperidine (11.1 mL, 100 mmol) in THF (25 mL) is addeddrop-wise, and the solution is stirred for 1 h at 40° C. The reaction isquenched with 40 mL 6N HCl, diluted with 250 mL ether, and a smallamount of sodium thiosulfate solution is added to remove the iodinecolor. The solution is neutralized with saturated NaHCO₃, filtered, andextracted with ether (3×150 mL). The combined organic layer is driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude material ischromatographed over 600 g slurry-packed silica, eluting with 20%EtOAc/hexane to afford 2-chloronicotinaldehyde (C90) as a pale orangesolid (54% yield). MS (EI) for C₆H₄ClNO, m/z: 141 (M)⁺.

C90 (1.41 g, 10.01 mmol) is dissolved in DMF (10 mL) and H₂O (1 mL)under N₂. K₂CO₃ (1.56 g, 11.27 mmol) and methyl thioglycolate (1.00 mL,11.25 mmol) are added portionwise. The reaction is stirred at 35° C. for24 h, quenched with cold H₂O (75 mL), and placed in an ice bath toenhance precipitation. The precipitate is isolated by filtration,affording methyl-thieno[2,3-b]pyridine-2-carboxylate (C101) as an orangepowder (40% yield). MS (EI) for C₉H₇NO₂S, m/z: 193 (M)⁺.

C101 (0.700 g, 3.63 mmol) is dissolved in MeOH (15 mL) and 3 mL H₂O. 2NNaOH (1.82 mL, 3.63 mmol) is added drop-wise, and the reaction isstirred at rt for 24 h. The reaction is concentrated in vacuo, and H₂O(40 mL) is added to dissolve the residue. The resulting solution isacidified to pH 4 using concentrated HCl, and the precipitate isisolated by filtration, yielding thieno[2,3-b]pyridine-2-carboxylic acid(C102) as a white powder (85% yield). MS (EI) for C₈H₅NO₂S, m/z: 179(M)⁺.

Example 13(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C102.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 13(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-2-carboxamide.

EXAMPLE 13(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-2-carboxamide.

EXAMPLE 13(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-2-carboxamide.

EXAMPLE 13(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-2-carboxamide.

EXAMPLE 13(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-b]pyridine-2-carboxamide.

EXAMPLE 13(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-b]pyridine-2-carboxamide.

EXAMPLE 14(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-5-carboxamide:

2-Nitrothiophene (33.76 g, 261.4 mmol) is suspended in concentrated HCl(175 mL) and heated to 50° C. Stannous chloride (118.05 g, 523.2 mmol)is added portionwise, maintaining the reaction temperature between45-50° C. with an ice bath, that is removed after the addition. Thesolution is allowed to cool slowly to 30° C. over an hour. The solutionis then cooled in an ice bath and filtered. The cake is washed withconcentrated HCl (20 mL), dried in a stream of air, and washed withether (50 mL) to afford the hexachlorostannate salt of 2-aminothiopheneas a brown solid (26% yield).

3,3-Dimethyl-2-forrnyl propionitrile sodium (3.33 g, 20.2 mmol) canreadily be prepared from the method described by Bertz, S. H., et al.,J. Org. Chem., 47, 2216-2217 (1982). 3,3-Dimethyl-2-formyl propionitrilesodium is dissolved in MeOH (40 mL), and concentrated HCl (4 mL) and thehexachlorostannate salt of 2-aminothiophene (10.04 g, 19.1 mmol) in MeOH(130 mL) is slowly added drop-wise to the mixture. Following addition,the mixture is heated to reflux in an oil bath (80° C.) for 4 h, andthen MeOH (10 mL) and concentrated HCl (10 mL) are added. The reactioncontinued refluxing for another 20 h. The solution is cooled to rt, andthe reaction is concentrated in vacuo. The purple residue is dissolvedin H₂O (60 mL), and the slurry is filtered. The cake is pulverized andstirred vigorously with 5% MeOH/CHCl₃ (105 mL) while heating to 55° C.The mixture is cooled and filtered, and the organic layer isconcentrated to a green oil. The crude material is chromatographed over130 g slurry-packed silica, eluting with 30% EtOAc/hexane to affordthieno[2,3-b]pyridine-5-carbonitrile (C105) as a pale yellow solid (24%yield). HRMS (FAB) calculated for C₉H₄N₂S+H: 161.0173, found 161.0173(M+H).

NaOH (0.138 g, 3.45 mmol) is added to a solution of C105 (0.503 g, 3.14mmol) dissolved in 70% EtOH/H₂O (12 mL). The mixture is heated to refluxat 100° C. for 3 h. The reaction is concentrated in vacuo, and theresidue is dissolved in H₂O (8 mL) and neutralized with concentratedHCl. The slurry is filtered and rinsed with ether. An initial NMR of theisolated material indicates the presence of the carboxamideintermediate, so the material is suspended in 1 M NaOH (6 mL) andstirred overnight. Water (10 mL) is added, the solution is extractedwith ether (3×10 mL), and the mixture is neutralized with concentratedHCl. The slurry is filtered and rinsed with ether, affording ofthieno[2,3-b]pyridine-5-carboxylic acid (C106) as an off-white solid(48% yield). MS (EI) for C₈H₅NO₂S, m/z: 179 (M)⁺.

Example 14(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C106.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 14(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-5-carboxamide.

EXAMPLE 14(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-5-carboxamide.

EXAMPLE 14(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-5-carboxamide.

EXAMPLE 14(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-5-carboxamide.

EXAMPLE 14(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-b]pyridine-5-carboxamide.

EXAMPLE 14(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-b]pyridine-5-carboxamide.

EXAMPLE 15(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-6-carboxamide:

2-Nitrothiophene (12.9 g, 99.9 mmol) is dissolved in concentrated HCl(200 mL) and stirred vigorously at 30° C. Granular tin (25 g, 210 mmol)is slowly added portionwise. When the tin is completely dissolved, zincchloride (6.1 g, 44.7 mmol) in EtOH (70 mL) is added drop-wise, themixture is heated to 85° C., and malondialdehyde diethyl acetal (24 mL,100 mmol) in EtOH (30 mL) is added. The solution continued stirring at85° C. for 1 h, and is quenched by pouring over ice (100 g). The mixtureis adjusted to pH 10 with NH₄OH, and the resulting slurry is carefullyfiltered through celite overnight. The liquor is extracted with CHCl₃(3×300 mL), and the combined organic layer is dried over MgSO₄,filtered, and concentrated to a brown oil. The crude material ischromatographed over 250 g slurry-packed silica, eluting with 35%EtOAc/hexane to give thieno[2,3-b]pyridine (C110) as an orange oil (26%yield). MS (EI) for C₇H₅NS, m/z: 135 (M)⁺.

C110 (3.47 g, 25.7 mmol) is dissolved in acetic acid (12 mL) and heatedto 85° C. 30% Hydrogen peroxide (9 mL) is added drop-wise and thesolution is allowed to stir overnight. The reaction is allowed to coolto rt and quenched with paraformaldehyde until a peroxide test provednegative using starch-iodine paper. The solution is diluted with H₂O(100 mL) and neutralized with NaHCO₃, then extracted repeatedly withCHCl₃ (12×80 mL, 6×50 mL). The combined organic layer is dried overNa₂SO₄, filtered, and concentrated to a brown solid. The crude materialis chromatographed over 70 g slurry-packed silica eluting with 3.5%MeOH/CH₂Cl₂ to afford thieno[2,3-b]pyridine-7-oxide (C111) as a paleyellow solid (22% yield). MS (ED) for C₇H₅NOS m/z: 151 (M)⁺.

A 0.5M solution of C111 (5 mL, 2.5 mmol) in CH₂Cl₂ is diluted with 8 mLof CH₂Cl₂ under N₂. Dimethyl carbamyl chloride (0.27 mL, 2.9 mmol) isadded drop-wise, followed by the addition of trimethylsilyl cyanide(0.388 mL, 2.9 mmol) via syringe. The reaction is allowed to stir for 9days and is quenched with 10% K₂CO₃ (10 mL). The layers are allowed toseparate, the organic layer is isolated and dried over K₂CO₃, filtered,and concentrated to a brown solid. The crude material is chromatographedover 25 g slurry-packed silica, eluting with 35% EtOAc/hexane to affordthieno[2,3-b]pyridine-6-carbonitrile (C112) as a pale yellow solid (100%yield). Analysis calculated for C₈H₄N₂S: C, 59.98; H, 2.52; N, 17.49,found: C, 59.91; H, 2.57; N, 17.43.

NaOH (398 mg, 9.95 mmol) is added portionwise to a solution of C112 (674mg, 4.2 mmol) in 70% EtOH/H₂O (20 mL). The solution is heated to refluxat 100° C. for 24 h, and the reaction is concentrated in vacuo. Theresidue is dissolved in H₂O (15 mL) and washed with ether (3×10 mL).Concentrated HCl is used to adjust the pH to 3.5, creating aprecipitate. The slurry is filtered, givingthieno[2,3-b]pyridine-6-carboxylic acid (C113) as a white solid (45%yield). MS (EI) for C₈H₅NO₂S, m/z: 179(M)⁺.

Example 15(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C113.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 15(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-b]pyridine-6-carboxamide.

EXAMPLE 15(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-6-carboxamide.

EXAMPLE 15(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-6-carboxamide.

EXAMPLE 15(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-6-carboxamide.

EXAMPLE 15(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-b]pyridine-6-carboxamide.

EXAMPLE 15(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-b]pyridine-6-carboxamide.

EXAMPLE 16(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-2-carboxamide:

THF (200 mL) is chilled to −70° C. in a dry flask under N₂, andN-butyllithium (24.4 mL, 55.0 mmol) is added drop-wise. The reaction isplaced in an ice bath and DIA (7.71 mL, 55.0 mmol) in THF (20 mL) isadded drop-wise. The solution is again chilled to −70° C., and3-chloropyridine (4.75 mL, 50.0 mmol) in THF (20 mL) is added drop-wise.The reaction is allowed to stir for 4 h at −70° C. and ethyl formate(4.44 mL, 55.0 mmol) in THF (20 mL) is added. The reaction is stirredfor an additional 3 h at −70° C. and quenched with H₂O (500 mL). Thelayers are allowed to separate, and the aqueous layer is extracted withEtOAc (3×250 mL). The combined organic layer is dried over MgSO₄,filtered, and concentrated to a dark brown solid. The crude material ischromatographed over 250 g slurry-packed silica, eluting with 50%EtOAc/hexane to give 3-chloroisonicotinaldehyde (C120) as an off-whitesolid (55% yield). MS (EI) for C₆H₄ClNO, m/z: 141 (M)⁺.

C120 (2.12 g, 14.9 mmol) is dissolved in DMF (75 mL) with a small amountof H₂O (7.5 mL). Methyl thioglycolate (1.67 mL, 18.7 mmol) and K₂CO₃(2.59 g, 18.7 mmol) are added portionwise, and the mixture is stirred at45° C. for 24 h. The reaction is quenched with cold H₂O (200 mL) andextracted with EtOAc (3×150 mL). The combined organic layer is washedwith 50% NaCl solution (3×150 mL), dried over MgSO₄, filtered, andconcentrated to an orange solid. The crude material is chromatographedover 40 g slurry-packed silica, eluting with 50% EtOAc/hexane to affordethyl thieno[2,3-c]pyridine-2-carboxylate (C121) as a pale yellow solid(22% yield).

C121 (577 mg, 2.99 mmol) is combined with 2M NaOH (1.5 mL, 3.0 mmol) inMeOH (15 mL) and H₂O (1.5 mL). The reaction is stirred at rt for 24 h.The reaction is concentrated in vacuo and the residue is dissolved inH₂O (75 mL). Concentrated HCl is used to acidify the solution to pH 3.The slurry is filtered, washed with H₂O and ether, and dried, affordingthieno[2,3-c]pyridine-2-carboxylic acid (C122) as an off-white solid(38% yield). HRMS (FAB) calculated for C₈H₅NO₂S+H: 180.0119, found180.0119 (M+H).

Example 16(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C122.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 16(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-2-carboxamide.

EXAMPLE 16(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-c]pyridine-2-carboxamide.

EXAMPLE 16(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-c]pyridine-2-carboxamide.

EXAMPLE 16(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-c]pyridine-2-carboxamide.

EXAMPLE 16(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-c]pyridine-2-carboxamide.

EXAMPLE 16(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-c]pyridine-2-carboxamide.

EXAMPLE 17(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-2-carboxamide:

3-Chloropyridine (9.5 mL. 99.9 mmol) is dissolved in acetic acid (35 mL)and heated to 98° C. 30% Hydrogen peroxide (28 mL) is added drop-wise,and the reaction stirred for 5 h at 98° C. The reaction is cooled andparaformaldehyde is added so that a negative peroxide test is achievedusing starch-iodine paper. The solution is concentrated in vacuo and thecrude paste is chromatographed over 600 g slurry-packed silica elutingwith 4 L of 2% MeOH/CH₂Cl₂, 2 L of 4% MeOH/CH₂Cl₂, and finally 1 L of10% MeOH/CH₂Cl₂ to afford 3-chloropyridine 1-oxide (C125) as a pale oil(100% yield).

A 2M solution of C125 (10 mL, 20 mmol) is combined with an additional 90mL of CH₂Cl₂. Dimethylcarbamoyl chloride (2.03 mL, 22.0 mmol) is addeddrop-wise, followed by the addition of trimethyl silylcyanide (2.93 mL,22.0 mmol) via syringe. The reaction is stirred at rt for 10 days and isquenched with 10% K₂CO₃ (100 mL). The layers are allowed to separate,and the organic layer is dried over K₂CO₃, filtered, and concentrated toan orange solid. The crude material is chromatographed over 160 gslurry-packed silica eluting with 40% EtOAc/hexane to yield3-chloropyridine-2-carbonitrile (C126) as a white solid (59% yield). MS(EI) for C₆H₃ClN₂, m/z: 138 (M)⁺.

C126 (1.01 g, 7.29 mmol) and K₂CO₃ (1.10 g, 7.96 mmol) are added to DMF(10 mL) and H₂O (1 mL). Methyl thioglycolate (0.709 mL, 7.93 mmol) isadded drop-wise, and the solution is heated to 40° C. and stirred for 3h. The reaction is quenched with cold H₂O (70 mL) and placed on ice toenhance precipitation. The slurry is filtered and the cake is dissolvedin CHCl₃. This organic solution is dried over MgSO₄, filtered, andconcentrated, affording methyl3-aminothieno[3,2-b]pyridine-2-carboxylate (C127) as a yellow solid (84%yield). HRMS (FAB) calculated for C₉H₈N₂O₂S+H: 209.0385, found 209.0383(M+H).

C127 (0.919 g, 4.42 mmol) is dissolved in 50% hypophosphorous acid (35mL) and chilled in an ice bath. Sodium nitrite (0.61 g, 8.84 mmol) isdissolved in a minimal amount of H₂O and added drop-wise to the previoussolution, and the reaction is stirred for 3 h in an ice bath. 3M NaOH isused to adjust the pH to 7.9, and the solution is extracted with EtOAc(3×100 mL). The combined organic layer is dried over MgSO₄, filtered,and concentrated to afford methyl thieno[3,2-b]pyridine-2-carboxylate(C128) as a yellow solid (44% yield). MS (EI) for C₉H₇NO₂S, m/z: 193(M)⁺.

2M NaOH (0.8 mL, 1.6 mmol) and C128 (300 mg, 1.55 mmol) are added toMeOH (8 mL) and H₂O (1 mL) and is stirred for 24 h. The reaction isconcentrated in vacuo, and the residue is dissolved with H₂O (5 mL). 5%HCl is used to adjust the pH to 3.5, creating a precipitate. The slurryis filtered and washed with ether, affordingthieno[3,2-b]pyridine-2-carboxylic acid (C129) as a brown solid (67%yield). HRMS (FAB) calculated for C₈H₅NO₂S+H: 180.0119, found 180.0121(M+H).

Example 17(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1] -3-Amine with C129.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 1 7(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-2-carboxamide.

EXAMPLE 17(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-2-carboxamide.

EXAMPLE 17(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-2-carboxamide.

EXAMPLE 17(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-2-carboxamide.

EXAMPLE 17(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-b]pyridine-2-carboxamide.

EXAMPLE 17(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-b]pyridine-2-carboxamide.

EXAMPLE 18(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-5-carboxamide:

Example 18(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with commercially-availablethieno[3,2-b]pyridine-5-carboxylic acid.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 18(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-5-carboxamide.

EXAMPLE 18(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-5-carboxamide.

EXAMPLE 18(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-5-carboxamide.

EXAMPLE 18(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-5-carboxamide.

EXAMPLE 18(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-b]pyridine-5-carboxamide.

EXAMPLE 18(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-b]pyridine-5-carboxamide.

EXAMPLE 19(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-6-carboxamide:

Methyl 3-aminothiophene-2-carboxylate (1.52 g, 9.68 mmol) is dissolvedin 2M NaOH (10 mL, 20 mmol) and heated to reflux in a 115° C. oil bathfor 30 min. The mixture is cooled to rt, placed in an ice bath, andcarefully acidified with concentrated HCl. The slurry is filtered andrinsed with H₂O (25 mL). The cake is then dissolved in acetone (50 mL),dried over MgSO₄, filtered, and concentrated to a thick paste. The crudematerial is dissolved in 1-propanol (25 mL), and oxalic acid (0.90 g,10.0 mmol) is added portionwise. The mixture is heated at 38° C. for 45min, cooled to rt, and diluted with ether. The precipitate is isolatedvia filtration, and washed with ether, affording 3-amino-thiopheneoxalate (C135) as a fluffy white solid (70% yield). HRMS (FAB)calculated for C₄H₅NS+H: 100.0221, found 100.0229 (M+H).

3,3-Dimethyl-2-formyl propionitrile sodium (5.38 g, 32.6 mmol) isdissolved in MeOH (60 mL) with concentrated HCl (6 mL). C135 (6.16 g,32.6 mmol) is suspended in MeOH (200 mL) and added drop-wise to theacidic solution. The mixture is heated to reflux at 80° C. for 5 h whenan additional 20 mL concentrated HCl and 20 mL H₂O are added; themixture continues refluxing for another 12 h. The mixture isconcentrated in vacuo, and the residue is dissolved with cold H₂O (100mL). The resulting precipitate is filtered off and dried, givingthieno[3,2-b]pyridine-6-carbonitrile (C136) as a brown solid (44%yield). HRMS (FAB) calculated for C₈H₄N₂S+H: 161.0173, found 161.0170(M+H).

C136 (1.99 g, 12.5 mmol) is dissolved in 70% EtOH/H₂O (20 mL), and NaOH(0.52 g, 13.0 mmol) is added portionwise. The mixture is heated at 100°C. for 15 h and then allowed to cool to rt. The mixture is concentratedin vacuo. The residue is dissolved in cold H₂O (30 mL), and the solutionis rinsed with ether (3×10 mL). The pH is adjusted to 3.5 withconcentrated HCl to precipitate the desired product that is removed byfiltration to give thieno[3,2-b]pyridine-6-carboxylic acid (C137) as atan solid (77% yield). HRMS (FAB) calculated for C₈H₅NO₂S+H: 180.0119,found 180.0118 (M+H).

Example 19(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C137.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 19(i)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-b]pyridine-6-carboxamide.

EXAMPLE 19(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-6-carboxamide.

EXAMPLE 19(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-6-carboxamide.

EXAMPLE 19(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-6-carboxamide.

EXAMPLE 19(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-b]pyridine-6-carboxamide.

EXAMPLE 1 9(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-b]pyridine-6-carboxamide.

EXAMPLE 20(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-2-carboxamide:

4-Chloropyridine hydrochloride (15 g, 99.9 mmol) is free-based bystirring in 1000 mL 1:1 saturated NaHCO₃/ether for 1 h. The layers areallowed to separate, the aqueous layer is extracted with ether (2×175mL), and the combined organic layer is dried over MgSO₄, filtered, andconcentrated to an oil. THF (300 mL) is chilled to −70° C. in a dryflask. N-butyllithium (105.1 mL, 168.2 mmol) is added drop-wise, and themixture is placed in an ice bath. Diisopropylamine (23.6 mL. 168.4 mmol)in THF (50 mL) is added drop-wise, the yellow solution is stirred for 30min, and the reaction is cooled to −70° C. The free-based4-chloropyridine oil (9.55 g, 84.1 mmol) is dissolved in THF (50 mL) andadded drop-wise to the chilled yellow solution, that turned dark redafter the addition. The reaction is stirred at −70° C. for 2 h. Ethylformate (13.6 mL, 168.3 mmol) in THF (25 mL) is then added drop-wise tothe dark solution at −70° C. After 2 hours, the reaction is warmed to−10° C. and quenched with water (450 mL). The layers are allowed toseparate, and the aqueous layer is extracted with ether (3×200 mL). Thecombined organic layer is dried over MgSO₄, filtered, and concentratedin vacuo to an oil. The crude material is chromatographed over 320 gslurry-packed silica eluting with 30% EtOAc/hexane to afford4-chloropyridine-3-carboxaldehyde (C140) an orange oil which solidifiedunder vacuum to an orange solid (21% yield).

C140 (2.53 g, 17.9 mmol) is dissolved in DMF (20 ni]L) and H₂O (2 mL).K₂CO₃ (2.97 g, 21.5 mmol) and methyl thioglycolate (1.92 mL, 21.5 mmol)are added portionwise. The reaction is stirred at 45° C. for 24 h, thenquenched with cold H₂O (100 mL), and the flask is placed on ice toenhance precipitation. The precipitate is isolated by filtration anddried, affording methyl thieno[3,2-c]pyridine-2-carboxylate (C141) as awhite solid (92% yield). MS (EI) for C₉H₇NO₂S, m/z: 193 (M)⁺.

C141 (2.65 g, 13.7 mmol) is dissolved in MeOH (70 mL) and H₂O (5 mL). 2NNaOH (6.86 mL, 13.7 mmol) is added drop-wise, and the reaction isstirred at rt for 24 h. The reaction is concentrated in vacuo, and H₂O(150 mL) is added to dissolve the residue. The resulting salt solutionis acidified to pH 3.5 using concentrated HCl, and the precipitate isisolated by filtration and dried, affordingthieno[3,2-c]pyridine-2-carboxylic acid (C142) as a white powder (57%yield). HRMS (FAB) calculated for C₈H₅NO₂S+H: 180.0119, found 180.0124(M+H).

Example 20(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C142.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 20(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-2-carboxamide.

EXAMPLE 20(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-c]pyridine-2-carboxamide.

EXAMPLE 20(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-c]pyridine-2-carboxamide.

EXAMPLE 20(iv)

N-(2-azabicyclo[2.2. I]hept-6-yl)-thieno[3,2-c]pyridine-2-carboxamide.

EXAMPLE 20(v)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-2-carboxamide.

EXAMPLE 20(vi)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-2-carboxamide.

EXAMPLE 21(i)

Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-5-carboxamide.fumarate:

Glyoxylic acid monohydrate (20.3 g, 221 mmol) and benzyl carbamate (30.6g, 202 mmol) are added to ether (200 mL). The solution is allowed tostir for 24 h at rt. The resulting thick precipitate is filtered, andthe residue is washed with ether, affording([(benzyloxy)carbonyl]amino)(hydroxy)acetic acid (C150) as a white solid(47% yield). MS (CI) for C₁₀H₁₁NO₅+H m/z: 226 (M+H).

C150 (11.6 g, 51.5 mmol) is dissolved in absolute MeOH (120 mL) andchilled in an ice bath. Concentrated sulfuric acid (2.0 mL) is carefullyadded drop-wise. The ice bath is allowed to expire as the solutionstirred for 2 days. The reaction is quenched by pouring onto a mixtureof 500 g ice with saturated NaHCO₃ solution (400 mL). The solution isextracted with EtOAc (3×300 mL), and the combined organic layer is driedover MgSO₄, filtered, and concentrated to a pale oil that crystallizedupon standing, giving methyl([(benzyloxy)carbonyl]amino)(methoxy)acetate(C151) as a white solid (94% yield). Analysis calculated for C₁₂H₁₅NO₅:C, 56.91; H, 5.97; N, 5.53, found: C, 56.99; H, 6.02; N, 5.60.

C151 (11.76 g, 46.4 mmol) is dissolved in toluene (50 mL) under N₂ andheated to 70° C. Phosphorous trichloride (23.2 mL, 46.4 mmol) is addeddrop-wise via syringe, and the solution is stirred for 18 h at 70° C.Trimethyl phosphite (5.47 mL, 46.4 mmol) is then added drop-wise, andstirring continued for an additional 2 h at 70° C. The mixture isconcentrated in vacuo to an oil, and the crude material is dissolved inEtOAc (100 mL) and washed with saturated NaHCO₃ (3×50 mL). The organiclayer is dried over Na₂SO₄, filtered, and concentrated to a volume of 30mL. This remaining solution is stirred vigorously while hexane is addeduntil a precipitate formed. The precipitated solid is removed byfiltration, affording methyl ([(benzyloxy)carbonyl]amino)(dimethoxyphosphoryl)acetate (C152) as a white solid (84% yield). MS(EI) for C₁₃H₁₈NO₇P, m/z: 331 (M)⁺.

C152 (12.65 g, 38.2 mmol) and acetic anhydride (9.02 mL, 95.5 mmol) inMeOH (100 mL) were added to a Parr flask. The solution is hydrogenatedwith 10% Pd/C catalyst (0.640 g) at 45 PSI for 3 h. The catalyst isfiltered off, and the filtrate is concentrated in vacuo to an oil. Theoil is placed under reduced pressure and solidified as the reducedpressure is applied. The white residue is dissolved in a small amount ofEtOAc and stirred vigorously while pentane is added until a precipitatebegan to form. The precipitate is removed by filtration to give methyl(acetylamino)(dimethoxyphosphoryl)acetate (C153) as a white powder (87%yield). MS (CI) for C₇H₁₄NO₆P, m/z: 240 (M+H).

2,3-Thiophene dicarboxaldehyde (1.40 g, 9.99 mmol) is dissolved inCH₂Cl₂ (100 mL) and the flask is placed in an ice bath. C152 (2.63 g,11.0 mmol) is dissolved in CH₂Cl₂ (50 mL),1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 mL, 11.0 mmol) is added, andthis solution is added drop-wise to the chilled thiophene solution. Thereaction mixture is stirred for 1 h while the flask is in an ice bathand then over night at rt. The reaction is concentrated in vacuo, andthe crude material is chromatographed over 300 g slurry-packed silicaeluting with 50% EtOAc/hexane. The fractions were collected in twodifferent groups to obtain the desired compounds. Each group offractions is combined and concentrated separately. The first group offractions affords methyl thieno[2,3-c]pyridine-5-carboxylate (C154) as awhite solid (41% yield), and the second group of fractions affordsmethyl thieno[3,2-c]pyridine-6-carboxylate (C155) as a yellow solid (38%yield). MS (EI) for C154 for C₉H₇NO₂S, m/z: 193 (M)⁺. MS (EI) for C155for C₉H₇NO₂S, m/z: 193 (M)⁺.

C154 (736 mg, 3.8 mmol) is dissolved in MeOH (16 mL) with water (2 mL).2M NaOH (2.0 mL, 4.0 mmol) is added drop-wise and the solution stirredat rt. After 2 days (complete disappearance of ester by TLC), thereaction is concentrated in vacuo. The residue is dissolved in H₂O (12mL), and the pH is adjusted to 3.5 with 10% HCl. The precipitated solidis removed by filtration, and the solid is rinsed with ether, affordingthieno[2,3-c]pyridine-5-carboxylic acid (C156) as a white solid (58%yield). HRMS (FAB) calculated for C₈H₅NO₂S+H: 180.0119, found 180.0123(M+H).

Coupling exo-(4S)-[2.2.1]-3-Amine with C156, followed by fumarate saltformation as described in Steps 1a and 1b, respectively, gives Example21(i) in 84% yield. MS for C₁₄H₁₆N₃OS (ESI) m/e: 274 (M+H).

EXAMPLE 21 (i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 21 (ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 21 (iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 21 (iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 21(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[2,3-c]pyridine-5-carboxamide:Yield from coupling is 66%. MS (EI) m/z 287 (M⁺).

EXAMPLE 21 (vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[2,3-c]pyridine-5-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 22(i)

Exo-4(S)—N-(1-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-6-carboxamide.fumarate:

Methyl thieno[3,2-c]pyridine-6-carboxylate (C155) (678 mg, 3.5 mmol) isdissolved in MeOH (16 mL) and H₂O (2 mL). 2M NaOH (1.8 mL, 3.6 mmol) isadded drop-wise, and the solution stirred at rt. After 2 days (completedisappearance of ester by TLC), the solution is concentrated in vacuo.The residue is dissolved in H₂O (12 mL), and the pH is adjusted to 3.5with 10% HCl. The precipitated solid is removed by filtration, and thesolid is rinsed with ether, affording thieno[3,2-c]pyridine-6-carboxylicacid (C160) as a white solid (43% yield). HRMS (FAB) calculated forC₈H₅NO₂S+H: 180.0119, found 180.0123 (M+H).

Example 22 is obtained by coupling exo-(4S)-[2.2.1]-3-Amine with C160,followed by fumarate salt formation as described in Steps 1a and 1b,respectively, to give Example 22(i) in 77% yield. MS for C₁₄H₁₆N₃SO(ESI) m/e: 274 (M+H).

EXAMPLE 22(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-thieno[3,2-c]pyridine-6-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 22(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-c]pyridine-6-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 22(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-c]pyridine-6-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 22(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-6-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 22(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-thieno[3,2-c]pyridine-6-carboxamide:Example 22(v) is made by coupling C160 with exo-[3.2.1]-Amine using thecoupling procedures described herein. Yield for coupling is 58%. MS (EI)m/z 287 (M⁺).

EXAMPLE 22(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-thieno[3,2-c]pyridine-6-carboxamide:This example can be prepared according to the coupling proceduresdiscussed herein.

EXAMPLE 23(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide:

2,4-Lutidine (51.4 mL, 0.445 mole) is added drop-wise to 250 mL fumingsulfuric acid in a flask under N₂ in an ice bath. The solution istreated portionwise with potassium nitrate (89.9 g, 0.889 mole) over a15 min period. The reaction is stirred 1 h in an ice bath, 2 h at rt, isgradually warmed in a 100° C. oil bath for 5 h, and then in a 130° C.oil bath for 4 h. The mixture is cooled, is poured into 1000 mL ice, andthe mixture is neutralized with NaHCO₃ (1,100 g, 13.1 mole). Theprecipitated Na₂SO₄ is removed by filtration, the solid is washed with500 mL H₂O and the filtrate is extracted with 4×500 mL ether. Thecombined organic layer is dried over MgSO₄ and is concentrated in vacuoto a yellow oil (50 g). The crude oil is distilled under vacuum toprovide three fractions: 16 g recovered 2,4-lutidine (85° C.), 16 g2,4-dimethyl-3-nitro-pyridine (C169) contaminated with 25%2,4-dimethyl-5-nitro-pyridine (135-145° C.), and 16 g2,4-dimethyl-5-nitro-pyridine (C170) contaminated with2,4-dimethyl-3-nitropyridine (145-153° C.). ¹H NMR of C169 (CDCl₃)δ2.33, 2.54, 7.10, 8.43 ppm. ¹H NMR of C170 (CDCl₃) δ2.61, 2.62, 7.16,9.05 ppm.

C170/C169 (75:25) (5.64 g, 37 mmol) is combined with benzeneselenicanhydride (8.2 g, 22.8 mmol) in 300 mL dioxane in a flask under N₂. Thereaction is warmed to reflux for 10 h, is cooled, and is concentrated toa dark yellow oil. The oil is chromatographed over 250 g silica gel(230-400 mesh) eluting with 15% EtOAc/hexane to afford2-formyl-4-methyl-5-nitropyridine (C171) (66% yield). HRMS (EI)calculated for C₇H₆N₂O₃: 166.0378, found 166.0383 (M⁺).

C171 (1.15 g, 6.9 mmol), p-toluene sulfonic acid (41 mg, 0.22 mmol), andethylene glycol (1.41 mL, 25 mmol) are added to 25 mL toluene in a flaskequipped with a Dean-Starke trap. The reaction is warmed to reflux for 2h, is cooled to rt, and is concentrated in vacuo to an oily residue. Thecrude oil is chromatographed over 40 g silica gel (Biotage), elutingwith 20% EtOAc/hexane to afford2-(1,3-dioxolan-2-yl)-4-methyl-5-nitropyridine (C172) (90% yield). MS(EI) for C₉H_(10 N) ₂O₄, m/z: 210 (M)⁺.

C172 (1.3 g, 6.2 mmol) and DMF dimethyl acetal (1.12 mL, 8.4 mmol) areadded to 15 mL DMF under N₂. The reaction is warmed to 90° C. for 3 h,is cooled, and the reaction is concentrated in vacuo. The residue iscombined with 1.25 g 5% Pd/BaSO₄ in 20 mL EtOH in a 250 mL Parr shakerbottle and the mixture is hydrogenated at ambient pressure until uptakeceased. The catalyst is removed by filtration, and the filtrate iscombined with 500 mg 10% Pd/C catalyst in a 250 mL Parr shaker bottle.The mixture is hydrogenated at ambient pressure for 1 h. No additionalhydrogen uptake is observed. The catalyst is removed by filtration, andthe filtrate is concentrated in vacuo to a tan solid. The crude materialis chromatographed over 50 g silica gel (230-400 mesh), eluting with 7%MeOH/CH₂Cl₂. The appropriate fractions are combined and concentrated toafford 5-(1,3-dioxolan-2-yl)-1H-pyrrolo[2,3-c]pyridine (C173) (69%yield). MS for C₁₀H₁₀N₂O₂, (EI) m/z: 190 (M)⁺.

C173 (800 mg, 4.21 mmol) is dissolved in 44 mL 10% aqueous acetonitrile.p-Toluene sulfonic acid (630 mg, 3.3 mmol) is added, and the mixture isheated to reflux for 5 h. The mixture is cooled to rt, is concentratedin vacuo, and the resultant residue is diluted with 15 mL saturatedNaHCO₃. A pale yellow solid is collected, washed with water, and isdried to afford 1H-pyrrolo[2,3-c]pyridine-5-carbaldehyde (C174) (81%yield). HRMS (FAB) calculated for C₈H₆N₂O+H: 147.0558, found 147.0564(M+H).

C174 (500 mg, 3.42 mmol) is dissolved in 1.5 mL formic acid. Thesolution is cooled in an ice bath, 30% aqueous hydrogen peroxide (722μL, 6.8 mmol) is added drop-wise, and the reaction is stirred 1 h in anice bath, and allowed to stand overnight at 5° C. The mixture is dilutedwith H₂O, the solid is collected, washed with H₂O and is dried to give522 mg of an off-white solid. The formate salt is added to 7 mL H₂O, 3mL 2N NaOH is added, and the pH is adjusted to 3 with 5% aqueous HCl.The precipitate is collected and is dried to afford1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (C176) (67% yield). HRMS(FAB) calculated for C₈H₆N₂O₂+H: 163.0508, found 163.0507 (M+H).

Example 23(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C176.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 23(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 23(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 23(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 23(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 23(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-IH-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 23(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 24(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide:

5-(1,3-Dioxolan-2-yl)-1H-pyrrolo[2,3-c]pyridine (C173) (1.05 g, 5.52mmol) is dissolved in 20 mL THF in a dried flask under N₂. 60% Sodiumhydride (243 mg, 6.07 mmol) is added, the reaction is stirred 30 min,methyl iodide (360 4 L, 5.8 mmol) is added, and the reaction is stirredovernight at rt. The reaction is concentrated in vacuo and the residueis partitioned between 10 mL saturated NaCl and CH₂Cl₂ (4×10 mL). Thecombined organic layer is dried over anhydrous K₂CO₃ and is concentratedin vacuo to a tan paste. The crude material is chromatographed over 50 gsilica gel (230-400 mesh) eluting with 5% MeOH/CH₂Cl₂. The appropriatefractions are combined and concentrated to afford5-(1,3-dioxolan-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (C175) (86%yield). HRMS (FAB) calculated for C₁₁H₁₂N₂O₂+H: 205.0977, found205.0983.

C175 (920 mg, 4.5 mmol) is dissolved in 25 mL 10% aqueous acetonitrilein a flask. p-Toluene sulfonic acid (630 mg, 3.3 mmol) is added, and themixture is heated to 90° C. for 8 h. The mixture is cooled to rt,concentrated in vacuo, and the residue is partitioned between 15 mLsaturated NaHCO₃ and CH₂Cl₂ (4×10 mL). The combined organic layer isdried over anhydrous K₂CO₃ and is concentrated in vacuo to afford1-methyl-pyrrolo[2,3-c]pyridine-5-carbaldehyde (C177) (99% yield). HRMS(FAB) calculated for C₉H₈N₂O+H: 161.0715, found 161.0711.

C177 (690 mg, 4.3 mmol) is dissolved in 2 mL formic acid. The solutionis cooled in an ice bath, 30% aqueous hydrogen peroxide (970 μL, 8.6mmol) is added drop-wise, and the reaction is stirred 1 h in an icebath, and allowed to stand overnight at 5° C. The mixture isconcentrated to dryness, is suspended in H₂O, and the pH is adjusted to7 with 2N NaOH. The mixture is concentrated to dryness, is dissolved inMeOH, and is passed over 15 mL 50W-Y,2 ion exchange resin (hydrogenform) eluting with 200 mL MeOH followed by 200 mL 5% Et₃N/MeOH. Thebasic wash is concentrated to dryness to afford1-methyl-pyrrolo[2,3-c]pyridine-5-carboxylic acid (C178) (78% yield).HRMS (FAB) calculated for C₉H₈N₂O₂+H: 177.0664, found 177.0672 (M+H).

Example 24(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with C178.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 24(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 24(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 24(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 24(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 24(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-1-methyl-lH-pyrrolo[2,3-c]pyridine-5-carboxamide.

EXAMPLE 25(i)

N-(exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide-.1.5fumarate

Furo[2,3-c]pyridin-5-ylmethyl acetate (5.17 g, 27.05 mmol) is dissolvedin CH₂Cl₂ (130 mL), layered with saturated NaHCO₃ (220 mL), treated withBr₂ (8.36 mL, 162.3 mmol) and stirred very slowly for 4.5 h at rt. Themixture is stirred vigorously for 30 min, is diluted with CH₂Cl₂ (100mL) and the layers separated. The aqueous layer is extracted with CH₂Cl₂(2×100 mL) and the combined organics are concentrated to a small volumeunder a stream of nitrogen. The solution is diluted with EtOH (200 mL),treated with K₂CO₃ (22.13 g, 160.1 mmol) and stirred for 2.5 days at rt.The mixture is concentrated to dryness, partitioned between 50%saturated NaCl (200 mL) and CH₂Cl₂ (5×200 mL), dried over Na₂SO₄ andconcentrated in vacuo to a yellow solid (6.07 g). The crude material isadsorbed onto silica gel (12 g) and chromatographed over 250 gslurry-packed silica gel, eluting with a gradient of 50% EtOAc/hexane to100% EtOAc. The appropriate fractions are combined and concentrated invacuo to afford 5.02 g (81%) of (3-bromofuro[2,3-c]pyridin-5-yl)methanolas a white solid. MS (EI) m/z: 227 (M⁺).

Oxalyl chloride (1.77 mL, 20.1 mmol) is combined with CH₂Cl₂ (60 mL) ina dried flask under nitrogen, cooled to −78° C., treated dropwise withDMSO (2.86 mL, 40.25 mmol) and stirred for 20 min. The cooled solutionis treated drop-wise with a solution of(3-bromofuro[2,3-c]pyridin-5-yl)methanol (4.0 mg, 17.5 mmol) in THF (50mL), stirred for 1 h, then treated drop-wise with Et₃N (12.2 mL, 87.5mmol). The mixture is stirred for 30 min at −78° C., then 30 min at 0°C. The mixture is washed with saturated NaHCO₃ (120 mL) and the organicsdried over K₂CO₃ and concentrated in vacuo to a dark yellow solid (3.91g). The crude material is chromatographed over 150 g slurry-packedsilica gel, eluting with 30% EtOAc/hexane. The appropriate fractions arecombined and concentrated in vacuo to afford 3.93 g (99%) of3-bromofuro[2,3-c]pyridine-5-carbaldehyde as a white solid. MS (EI) m/z:225 (M⁺).

3-Bromofuro[2,3-c]pyridine-5-carbaldehyde (3.26 g, 14.42 mmol) isdissolved in THF (100 mL)/t-BuOH (50 mL)/H₂O (50 mL), treated with asingle portion of NaOCl₂ (4.89 g, 43.3 mmol) and KH₂PO₄ (3.92 g, 28.8mmol) and stirred at rt for 18 h. The white solid is collected viafiltration and the filtrate is concentrated in vacuo to dryness. Theresidue is suspended in water (25 mL), acidified to pH 2 withconcentrated HCl and the resulting solid collected via filtration. Thecollected solids are dried in a vacuum oven at 50° C. for 18 h andcombined to afford 3.52 g (99%) of3-bromofuro[2,3-c]pyridine-5-carboxylic acid as a white solid. MS (EI)m/z: 241 (M⁺).

To a stirred suspension of 3-bromofuro[2,3-c]pyridine-5-carboxylic acid(182 mg, 0.75 mmol) in DMF (10 mL) are added DIEA (400 μL, 2.30 mmol)and exo-4(S)-[2.2.1]-3-Amine (343 mg, 0.75 mmol). The mixture is cooledin an ice bath to 0° C., and HATU (286 mg, 0.75 mmol) is added in oneportion. The reaction mixture is allowed to warm to rt and stirovernight. The solvent is removed in vacuo, and the residue ispartitioned between saturated aqueous K₂CO₃ solution andchloroform-methanol (95:5). The aqueous layer is extracted withchloroform (3×). The combined organic layers are washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to give 50 mg(20%) of the amide as a white solid.

To a stirred solution of the above amide (50 mg, 0.15 mmol) in MeOH (5mL) is added a solution of fumaric acid (66 mg, 0.35 mmol) in MeOH (5mL). The solvent is removed in vacuo, and the remaining residue isdiluted with acetone (5 mL). The mixture is stirred overnight at rt. Thesolid precipitate is collected by filtration, washed with ether, anddried in vacuo overnight to give 53 mg (70%) of Example 25(i) as a whitesolid: ¹H NMR (400 MHz, CD₃OD) δ8.97, 8.36, 8.31, 6.72, 4.35-4.34,3.78-3.72, 3.55-3.36, 3.28-3.25, 3.09, 2.25-2.17, 1.92-1.85.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 25(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 25(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 25(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 25(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 25(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 26(i)

N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chlorofuro[2,3-c]pyridine-5-carboxamide.fumarate:

Furo[2,3-c]pyridin-5-ylmethanol (7.70 g, 51.63 mmol) is dissolved inpyridine (45 mL), treated with acetic anhydride (14.36 mL, 154.9 mmol)and stirred for 18 h at rt. The pyridine is removed in vacuo and theresulting residue dissolved in EtOAc (200 mL), washed with 50% saturatedsodium bicarbonate (4×90 mL), dried over MgSO₄ and concentrated in vacuoto afford 9.32 g (94%) of furo[2,3-c]pyridin-5-ylmethyl acetate as ayellow oil. MS (EI) m/z: 191 (M⁺), 277, 148, 119, 118, 86, 84, 77, 63,51, 50..

Furo[2,3-c]pyridin-5-ylmethyl acetate (956 mg, 5 mmol) is dissolved inCH₂Cl₂ (40 mL) and cooled to 0° C. Chlorine gas is bubbled through thesolution for 15 min, the cooling bath is immediately removed and themixture stirred for 2 h. The mixture is re-cooled to 0° C., saturatedwith chlorine gas, the cooling bath removed and the solution warmed tort. The solution is layered with saturated NaHCO₃ (20 mL), stirredgently for 2 h then stirred vigorously for 15 min. The mixture isdiluted with saturated NaHCO₃ (50 mL), extracted with CH₂Cl₂ (1×40 mLthen 1×20 mL), dried over K₂CO₃ and concentrated to a volume of 20 mLunder a stream of nitrogen. The solution is diluted with ETOH (35 mL),treated with K₂CO₃ (4.09 g, 29.6 mmol) and stirred for 18 h at rt. Water(7 mL) is added and the mixture stirred for 2 days. The mixture isconcentrated to dryness, partitioned between 50% saturated NaCl (50 mL)and CH₂Cl₂ (4×50 mL), dried over K₂CO₃ and concentrated in vacuo to abrown solid (833 mg). The crude material is chromatographed over astandard 40 g Biotage column, eluting with 50% EtOAc/hexane. Theappropriate fractions are combined and concentrated to afford 624 mg(68%) of (3-chlorofuro[2,3-c]pyridin-5-yl)methanol as a yellow oil. ¹HNMR (DMSO-d₆): δ4.69, 5.56, 7.69, 8.55, 8.93 ppm.

Oxalyl chloride (231 μL, 2.6 mmol) is combined with CH₂Cl₂ (10 mL),cooled to −78° C., treated dropwise with DMSO (373 μL, 5.3 mmol) andstirred for 20 min. The cooled solution is treated dropwise with asolution of (3-chlorofuro[2,3-c]pyridin-5-yl)methanol (420 mg, 2.3 mmol)in THF (5 mL)/CH₂Cl₂ (5 mL), stirred for 1 h, then treated dropwise withEt₃N (1.59 mL, 11.45 mmol). The mixture is stirred for 30 min at −78°C., then 30 min at 0° C. The mixture is washed with saturated NaHCO₃ (20mL) and the organics dried over K₂CO₃ and concentrated in vacuo to ayellow solid (410 mg). The crude material is chromatographed over 20 gslurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriatefractions are combined and concentrated in vacuo to afford 322 mg (77%)of 3-chlorofuro[2,3-c]pyridine-5-carbaldehyde as a white solid. ¹H NMR(CDCl₃): δ7.89, 8.33, 9.02, 10.18 ppm.

3-Chlorofuro[2,3-c]pyridine-5-carbaldehyde (317 mg, 1.74 mmol) isdissolved in THF (10 mL)/t-BuOH (5 mL)/H₂O (5 mL), treated with a singleportion of sodium chlorite (592 mg, 5.24 mmol) and KH₂PO₄ (473 mg, 3.48mmol) and stirred at rt for 18 h. The reaction mixture is concentratedin vacuo to dryness, suspended in water (10 mL), acidified to pH 3.5with concentrated HCl and stirred at rt for 2 h. The resulting solid isfiltered, washed with water and dried in a vacuum oven at 40° C. for 18h to afford 364 mg of 3-chlorofuro[2,3-c]pyridine-5-carboxylic acid as awhite solid. MS (EI) m/z: 197 (M⁺).

To a stirred solution of 3-chlorofuro[2,3-c]pyridine-5-carboxylic acid(99 mg, 0.5 mmol) in anhydrous DMF (10 mL) are added DIEA (265 μL, 1.52mmol) and exo-4(S)-[2.2.1]-3-Amine (228 mg, 0.5 mmol). The mixture iscooled in an acetone/icewater bath to −5° C., and HATU (190 mg, 0.5mmol) is added in one portion. The reaction mixture is allowed to warmto rt and stir overnight. The solvent is removed in vacuo, and theresidue is partitioned between saturated aqueous K₂CO₃ solution andchloroform. The aqueous layer is extracted with chloroform (2×). Thecombined organic layers are washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to give the amide as a white solid(125 mg, 85%).

To a stirred solution of the above amide (125 mg, 0.43 mmol) in acetone(5 mL) is added a warm solution of fumaric acid (49.7 mg, 0.43 mmol) inisopropanol (5 mL). The mixture is warmed to 50° C. for 10 min. Thesolvents are removed in vacuo, and the remaining residue is diluted withacetone (5 mL). The mixture is stirred overnight at rt. The solid iscollected by filtration, washed with acetone, and dried under highvacuum overnight to give 152 mg (87%) of Example 26(i) as a white solid:¹H NMR (400 MHz, CD₃OD) δ8.98, 8.42, 8.32, 6.71, 4.32-4.29, 3.73-3.68,3.50-3.35, 3.26-3.20, 3.07, 2.22-2.13, 1.89-1.81.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 26(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 26(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 26(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 26(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 26(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide.

EXAMPLE 27(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide:

N-butyl lithium (150.6 ml, 241 mmol) is added dropwise to ether (100 ml)at −20° C. under N₂. 3-Bromothianaphthene (10.5 ml, 80.3 mmol) isdissolved in ether (50 ml) and also added dropwise to the chilledsolution, stirring cold for 0.5 h. DMF (16.3 ml, 210 mmol) is dissolvedin ether (75 ml) and added dropwise, and the solution stirred anadditional 15 h at −20° C. The reaction is quenched onto ice (300 g) in10% H₂SO₄ (200 ml) and stirred until both layers turn yellow in color.The resulting slurry is filtered, and the cake is allowed to dry in theair stream, affording 1-benzothiophene-2,3-dicarbaldehyde (C180) as ayellow solid (60% yield). HRMS (FAB) calculated for C₁₀H₆O₂S+H:191.0167, found 191.0172 (M+H).

1-Benzothiophene-2,3-dicarbaldehyde (C180) (1.91 g, 10.0 mmol) isdissolved in CH₂Cl₂ (100 ml) and chilled in an ice bath. Methyl(acetylamino)(dimethoxyphosphoryl) acetate (C152) (2.63 g, 11.0 mmol) isdissolved in CH₂Cl₂ (50 ml) and added to1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 ml, 11.0 mmol), stirring for 5minutes. This solution is added dropwise to the chilled thiophenesolution. The reaction mixture is stirred in the ice bath for 1 h andthen over night at rt. The reaction is concentrated in vacuo and thecrude material is chromatographed over 500 g slurry-packed silicaeluting with 50% ethyl acetate/hexane to afford methylbenzothieno[3,2-c]pyridine-3-carboxylate (C181) as a white solid (73%yield). MS for C₁₃H₉NO₂S, (EI) m/z: 243 (M)⁺.

C181 (1.43 g, 5.87 mmol) is dissolved in MeOH (25 ml) with H₂O (3 ml).2M NaOH (3.0 ml, 6.0 mmol) is added dropwise and the solution stirred atrt. After 4 days (complete disappearance of ester by TLC), the reactionis concentrated in vacuo. The residue is dissolved in H₂O (5 ml) and thepH is adjusted to 3 with 10% HCl. The solution is stirred over nightbefore precipitation is complete. The slurry is filtered and the cake isrinsed with ether, giving a 100% yield ofbenzothieno[3,2-c]pyridine-3-carboxylic acid (C182)as a white solid.HRMS (FAB) calculated for C₁₂H₇NO₂S+H 230.0276, found 230.0275 (M+H).

Example 27(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with (C182).

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 27(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide.

EXAMPLE 27(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide.

EXAMPLE 27(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)-benzothieno[3,2-c]pyridine-3-carboxamide.

EXAMPLE 27(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)-benzothieno[3,2-c]pyridine-3-carboxamide.

EXAMPLE 27(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide.

EXAMPLE 27(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide.

EXAMPLE 28(i)

N-(1-azabicyclo[2.2.1]hept-3-yl)thieno[3,4-c]pyridine-6-carboxamide:

3,4-Dibromothiophene (12.5 ml, 113 mmol) is combined with CuCN (30.4 g,339 mmol) in DMF (40 ml) in a dry flask under nitrogen utilizing anover-head stirrer. The reaction is allowed to reflux at 180° C. for 5 h.The dark mixture is then poured into a solution of FeCl₃ (113.6 g, 700mmol) in 1.7M HCl (200 ml) and heated at 65° C. for 0.5 h, again usingthe over-head stirrer. The reaction is cooled to rt and extracted withCH₂Cl₂ (7×300 ml). Each extract is washed individually with 200 ml each6M HCl (2×), water, saturated NaHCO₃, and water. The organics are thencombined, dried over MgSO₄, filtered, and concentrated, affording 10.49g (69%) of 3,4-dicyanothiophene as a fluffy tan solid. HRMS (EI) calcdfor C₆H₂N₂S: 133.9939, found 133.9929 (M⁺).

3,4-Dicyanothiophene (5.0 g, 37.2 mmol) is suspended in benzene (150 ml)in a dry flask under nitrogen utilizing an over-head stirrer. Diisobutylaluminum hydride (1.0M in toluene) (82.0 ml, 82.0 mmol) is addeddropwise, and the reaction stirred at rt for 2 h. The reaction is thencarefully quenched with MeOH (5 ml) and poured onto 30% H₂SO₄ (60 ml)with ice (200 g). The slurry is stirred until all lumps are dissolved,and the layers are allowed to separate. The aqueous layer is extractedwith Et₂O (4×200 ml), and the combined organics are dried over MgSO₄,filtered, and adsorbed onto silica. The crude material ischromatographed over 225 g slurry-packed silica, eluting with 40%EtOAc/hexane. The appropriate fractions are combined and concentrated toafford 1.88 g (36%) of 3,4-thiophene dicarboxaldehyde as a pale yellowsolid. MS (EI) m/z: 140 (M⁺).

3,4-Thiophene dicarboxaldehyde (1.0 g, 7.13 mmol) is dissolved in CH₂Cl₂(40 ml) and chilled to 0° C. Methyl(acetylamino)(dimethoxyphosphoryl)acetate (1.88 g, 7.85 mmol) isdissolved in CH₂Cl₂ (30 ml) and combined with DBU (1.1 ml, 7.85 mmol).This solution is added dropwise to the chilled thiophene solution afterstirring for 5 min. The reaction mixture is stirred at 0° C. for 1 h andthen overnight at rt. The volatiles are removed in vacuo and the crudematerial is chromatographed over 68 g slurry-packed silica eluting with70% EtOAc/hexane. The appropriate fractions are combined andconcentrated to yield 2.09 g of the carbinol intermediate as a whitefoam. The intermediate is dissolved in CHCl₃ (50 ml) and treated withDBU (1.32 ml, 8.8 mmol) and trifluoracetic anhydride (1.24 ml, 8.8 mmol)in a drop-wise fashion. The reaction is stirred overnight at rt and isthen quenched with saturated NaHCO₃ solution (50 ml). The layers areseparated, and the aqueous layer is extracted with CHCl₃ (2×50 ml). Thecombined organics are dried over MgSO₄, filtered, and concentrated to ayellow oil. This oil is chromatographed over 50 g slurry-packed silica,eluting with 90% EtOAc/hexane. The appropriate fractions are combinedand concentrated to afford 1.2 g (88%) of methylthieno[3,4-c]pyridine-6-carboxylate as a yellow solid. MS (EI) m/z: 193(M⁺).

Methyl thieno[3,4-c]pyridine-6-carboxylate (250 mg, 1.3 mmol) isdissolved in MeOH (7 ml) and water (1 ml). 2M NaOH (0.72 ml, 1.43 mmol)is added drop-wise. The reaction is stirred overnight at rt and ismonitored by TLC. The volatiles are removed in vacuo and the residue isdissolved in water (2 ml). 10% HCl is used to adjust the pH to 3, andthe reaction again stirred overnight at rt. The aqueous solution isextracted repeatedly with EtOAc (20×10 ml). The combined organics aredried over MgSO₄, filtered, and concentrated to a yellow solid. Theamount of isolated product via extraction is minimal (67 mg), so theaqueous layer is concentrated and found to contain the majority ofproduct. Extraction of the solid aqueous residue with EtOAc provided 225mg (97%) of thieno[3,4-c]pyridine-6-carboxylic acid as a yellow solid.MS (EI) m/z: 179 (M⁺).

Example 28(i) can be obtained by coupling either exo-[2.2.1]-3-Amine orendo-[2.2.1]-3-Amine with thieno[3,4-c]pyridine-6-carboxylic acid usingprocedures discussed herein.

The following examples can be prepared according to the couplingprocedures discussed herein:

EXAMPLE 28(i-a)

N-(1-(6-methyl)-azabicyclo[2.2.1]hept-3-yl)thieno[3,4-c]pyridine-6-carboxamide.

EXAMPLE 28(ii)

N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)thieno[3,4-c]pyridine-6-carboxamide.

EXAMPLE 28(iii)

N-(2-azabicyclo[2.2.1]hept-5-yl)thieno[3,4-c]pyridine-6-carboxamide.

EXAMPLE 28(iv)

N-(2-azabicyclo[2.2.1]hept-6-yl)thieno[3,4-c]pyridine-6-carboxamide.

EXAMPLE 28(v)

N-((3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)thieno[3,4-c]pyridine-6-carboxamide.

EXAMPLE 28(vi)

N-(1-azabicyclo[3.2.2]non-3-yl)thieno[3,4-c]pyridine-6-carboxamide.

Materials and Methods for Determining α7 nAChR Agonist Activity

Cell-Based Assay for Measuring the EC₅₀ of α7 nAChR Agonists

Construction and Expression of the α7-5HT₃ Receptor:

The cDNA encoding the N-terminal 201 amino acids from the human α7 nAChRthat contain the ligand binding domain of the ion channel was fused tothe cDNA encoding the pore forming region of the mouse 5HT₃ receptor asdescribed by Eisele J L, et al., Chimaeric nicotinic-serotonergicreceptor combines distinct ligand binding and channel specificities,Nature (1993), December 2;366(6454):479-83, and modified by Groppi, etal., WO 00/73431. The chimeric α7-5HT₃ ion channel was inserted intopGS175 and pGS179 which contain the resistance genes for G-418 andhygromycin B, respectively. Both plasmids were simultaneouslytransfected into SH-EP1 cells and cell lines were selected that wereresistant to both G-418 and hyrgromycin B. Cell lines expressing thechimeric ion channel were identified by their ability to bindfluorescent α-bungarotoxin on their cell surface. The cells with thehighest amount of fluorescent α-bungarotoxin binding were isolated usinga Fluorescent Activated Cell Sorter (FACS). Cell lines that stablyexpressed the chimeric α7-5HT₃ were identified by measuring fluorescentα-bungarotoxin binding after growing the cells in minimal essentialmedium containing nonessential amino acids supplemented with 10% fetalbovine serum, L-glutamine, 100 units/ml penicillin/streptomycin, 250ng/mg fungizone, 400 μg/ml hygromycin B, and 400 μg/ml G-418 at 37° C.with 6% CO₂ in a standard mammalian cell incubator for at least 4 weeksin continuous culture.

Assay of the Activity of the Chimeric α7-5HT₃ Receptor

To assay the activity of the α7-5HT₃ ion channel, cells expressing thechannel were plated into each well of either a 96 or 384 well dish(Corning #3614) and grown to confluence prior to assay. On the day ofthe assay, the cells were loaded with a 1:1 mixture of 2 mM CalciumGreen 1, AM (Molecular Probes) dissolved in anhydrous DMSO and 20%pluronic F-127 (Molecular Probes). This solution was added directly tothe growth media of each well to achieve a final concentration 2 μM. Thecells were incubated with the dye for 60 min at 37° C. and then washedwith a modified version of Earle's balanced salt solution (MMEBSS) asdescribed in WO 00/73431. The ion conditions of the MMEBSS was adjustedto maximize the flux of calcium ion through the chimeric α7-5HT₃ ionchannel as described in WO 00/73431. The activity of compounds on thechimeric α7-5HT₃ ion channel was analyzed on FLIPR. The instrument wasset up with an excitation wavelength of 488 nanometers using 500milliwatts of power. Fluorescent emission was measured above 525nanometers with an appropriate F-stop to maintain a maximal signal tonoise ratio. Agonist activity of each compound was measured by directlyadding the compound to cells expressing the chimeric α7-5HT₃ ion channeland measuring the resulting increase in intracellular calcium that iscaused by the agonist-induced activation of the chimeric ion channel.The assay is quantitative such that concentration-dependent increase inintracelluar calcium is measured as concentration-dependent change inCalcium Green fluorescence. The effective concentration needed for acompound to cause a 50% maximal increase in intracellular calcium istermed the EC₅₀. The following examples were tested and have EC₅₀ valuesfrom about 40 nM to about 1200 nM: Example 1(i), Example 1(i-b), Example1(i-d), Example 1(v), Example 1(vi), Example 2(v), Example 7(i), Example7(v), Example 8(i), Example 11(i), Example 21(i), Example 21(v), Example22(i), Example 22(v), Example 25(i), and Example 26(i).

Binding Constants:

Another way for measuring α7 nAChR agonist activity is to determinebinding constants of a potential agonist in a competition binding assay.For α7 nAChR agonists, there is good correlation between functional EC₅₀values using the chimeric α7-5HT₃ ion channel as a drug target andbinding affinity of compounds to the endogenous α7 nAChR.

Membrane Preparation.

Male Sprague-Dawley rats (300-350g) are sacrificed by decapitation andthe brains (whole brain minus cerebellum) are dissected quickly, weighedand homogenized in 9 volumes/g wet weight of ice-cold 0.32 M sucroseusing a rotating pestle on setting 50 (10 up and down strokes). Thehomogenate is centrifuged at 1,000×g for 10 minutes at 4° C. Thesupernatant is collected and centrifuged at 20,000×g for 20 minutes at4° C. The resulting pellet is resuspended to a protein concentration of1-8 mg/mL. Aliquots of 5 mL homogenate are frozen at −80° C. untilneeded for the assay. On the day of the assay, aliquots are thawed at rtand diluted with Kreb's −20 mM Hepes buffer pH 7.0 (at rt) containing4.16 mM NaHCO₃, 0.44 mM KH₂PO₄, 127 mM NaCl, 5.36 mM KCl, 1.26 mM CaCl₂,and 0.98 mM MgCl₂, so that 25-150 μg protein are added per test tube.Proteins are determined by the Bradford method (Bradford, M. M., Anal.Biochem., 72, 248-254, 1976) using bovine serum albumin as the standard.

Binding Assay.

For saturation studies, 0.4 mL homogenate are added to test tubescontaining buffer and various concentrations of radioligand, and areincubated in a final volume of 0.5 mL for 1 hour at 25° C. Nonspecificbinding was determined in tissues incubated in parallel in the presenceof 0.05 mls MLA for a final concentration of 1 μM, added before theradioligand. In competition studies, drugs are added in increasingconcentrations to the test tubes before addition of 0.05 mls [³H]-MLAfor a final concentration 3.0 to 4.0 nM. The incubations are terminatedby rapid vacuum filtration through Whatman GF/B glass filter papermounted on a 48 well Brandel cell harvester. Filters are pre-soaked in50 mM Tris HCl pH 7.0-0.05% polyethylenimine. The filters are rapidlywashed two times with 5 mL aliquots of cold 0.9% saline and then countedfor radioactivity by liquid scintillation spectrometry.

Data Analysis.

In competition binding studies, the inhibition constant (Ki) wascalculated from the concentration dependent inhibition of [³H]-MLAbinding obtained from non-linear regression fitting program according tothe Cheng-Prusoff equation (Cheng, Y. C. and Prussoff, W. H., Biochem.Pharmacol., 22, p. 3099-3108, 1973). Hill coefficients were obtainedusing non-linear regression (GraphPad Prism sigmoidal dose-response withvariable slope).

1. A compound of the Formula I:

wherein Azabicyclo is

 provided that the bond between the —C(═X)— group and the W group may beattached at any available carbon atom within the W group as provided inR₃, R₆, and R₁₅; X is O, or S; R₀ is H, lower alkyl, substituted loweralkyl, or halogenated lower alkyl; Each R₁ is H, alkyl, cycloalkyl,halogenated alkyl, substituted phenyl, or substituted naphthyl; Each R₂is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, aryl, F, Cl,Br, I, or R₂ is absent provided that k₂, k₅, or k₆ is 0; R₂₋₃ is H,alkyl, substituted alkyl, halogenated alkyl, F, Cl, Br, or I; k₂ is 0 or1; k₅ and k₆ are independently 0, 1, or 2; A---A′---A″ isN(R₄)—C(R₃)═C(R₃), N═C(R₃)—C(R₁₅)₂, C(R₃)═C(R₃)—N(R₄), C(R₃)₂—N(R₄)—C(R₃)₂, C(R₁₅)₂—C(R₃)═N, N(R₄)—C(R₃)₂—C(R₃)₂, C(R₃)₂—C(R₃)₂—N(R₄),O—C(R₃)═C(R₃), O—C(R₃)₂—C(R₃)₂, C(R₃)₂—O—C(R₃)₂, C(R₃)═C(R₃)—O,C(R₃)₂—C(R₃)₂—O, S—C(R₃)═C(R₃), S—C(R₃)₂—C(R₃)₂, C(R₃)₂—S—C(R₃)₂,C(R₃)═C(R₃)—S, or C(R₃)₂—C(R₃)₂—S; Each R₃ is independently a bond tothe core molecule provided that only one R₃ and no R₆ or R₁₅ is alsosaid bond, H, alkyl, substituted alkyl, halogenated alkyl, alkenyl,substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl,halogenated alkynyl, —CN, —NO₂, F, Br, Cl, I, —OR₁₉, —C(O)N(R₁₀)₂,—N(R₁₀)₂, —SR₁₉, —S(O)₂R₁₉, —C(O)R₁₉, —CO₂R₁₉, aryl, R₇, or R₉; J, L, M,and Q are N or C(R₆) provided that only one of J, L, M, or Q, is N andthe others are C(R₆), further provided that when the core molecule isattached to the pyridinyl moiety at M, Q is C(H), and further providedthat there is only one attachment to the core molecule; G and Y areC(R₆), provided that when the molecule is attached to the phenyl moietyat Y, G is CH; R₄ is H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, or R₉; Each R₅ is independently H, lower alkyl, orlower alkenyl; Each R₆ is independently H, F, Br, I, Cl, —CN, —CF₃,—OR₅, —SR₅, —N(R₅)₂, or a bond to the core molecule provided that onlyone R₆ and no R₃ or R₁₅ is said bond; V is selected from O, S, or N(R₄);R₇ is 5-membered heteroaromatic mono-cyclic moieties containing withinthe ring. 1-3 heteroatoms independently selected from the groupconsisting of ═N—, —N(R₁₇)—, —O—, and —S—, and having 0-1 substituentselected from R₁₈ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I, or R₇ is 9-membered fused-ring moietieshaving a 6-membered ring fused to a 5-membered ring including theformula

 wherein G₁ is O, S or NR₁₇,

 wherein G is C(R₁₆) or N, and each G₂ and G₃ are independently selectedfrom C(R₁₆)₂, C(R₁₆), O, S, N, and N(R₁₈), provided that both G₂ and G₃are not simultaneously O, simultaneously S, or simultaneously O and S,or

 wherein G is C(R₁₆) or N, and each G₂ and G₃ are independently selectedfrom C(R₁₆)₂, C(R₁₆), O, S, N, and N(R₁₇), each 9-membered fused-ringmoiety having 0-1 substituent selected from R₁₈ and further having 0-3substituent(s) independently selected from F, Cl, Br, or I, wherein theR₇ moiety attaches to other substituents as defined in formula I at anyposition on either ring as valency allows; Each R₈ is independently H,alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenatedcycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenatedheterocycloalkyl, substituted heterocycloalkyl, R₇, R₉, phenyl, orsubstituted phenyl; R₉ is 6-membered heteroaromatic mono-cyclic moietiescontaining within the ring 1-3 heteroatoms selected from ═N— and having0-1 substituent selected from R₁₈ and 0-3 substituent(s) independentlyselected from F, Cl, Br, or I, or R₉ is 10-membered heteroaromaticbi-cyclic moieties containing within one or both rings 1-3 heteroatomsselected from ═N—, including, but not limited to, quinolinyl orisoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituentselected from R₁₈ and 0-3 substituent(s) independently selected from F,Cl, Br, or I, and having a bond directly or indirectly attached to thecore molecule where valency allows; Each R₁₀ is independently H, alkyl,cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituentselected from R₁₃, cycloalkyl substituted with 1 substituent selectedfrom R₁₃, heterocycloalkyl substituted with 1 substituent selected fromR₁₃, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, phenyl, or substituted phenyl; Each R₁₁ isindependently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, or halogenated heterocycloalkyl; R₁₂ is —NO₂,—CN, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substitutedcycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —N R₁₁R₁₁,—C(O)R₁₁, —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁;R₁₃ is —CN, —CF₃, —NO₂, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁,—NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁; Each R₁₄ is H, alkyl,substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl,halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl,F, Br, Cl, I, —CN, —NO₂, —OR₁₉, —C(O)N(R₁₀)₂, —N(R₁₀)₂, —SR₁₉,—S(O)₂R₁₉, —C(O)R₁₉ , —CO₂R₁₉, aryl, R₇ or R₉; Each R₁₅ is independentlyalkyl, substituted alkyl, halogenated alkyl, alkenyl, substitutedalkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenatedalkynyl, F, Br, Cl, I, —CN, —NO_(2,)—OR₁₉, —C(O)N(R₁₀)₂, —N(R₁₀)₂,—SR₁₉, —CO₂R₁₉, aryl, R₇, R₉, or a bond to the core molecule providedthat only one R₁₅ and no R₆ or R₃ is said bond; Each R₁₆ isindependently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, F, Cl, Br, I,—NO₂, —CN, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, or a bond directly or indirectly attachedto the core molecule, provided that there is only one said bond to thecore molecule within the 9-membered fused-ring moiety, further providedthat the fused-ring moiety has 0-1 substituent selected from alkyl,cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl,substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —NO₂,—C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁, andfurther provided that the fused-ring moiety has 0-3 substituent(s)selected from F, Cl, Br, or I; R₁₇ is H, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, halogenated cycloalkyl, substitutedcycloalkyl, phenyl, —SO₂R₈, or phenyl having 1 substituent selected fromR₁₈ and further having 0-3 substituents independently selected from F,Cl, Br, or I; R₁₈ is alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, —OR₁₁,—SR₁₁, —NR₁₁R₁₁, —C(O)R₁₁, —C(O)NR₁₁R₁₁, —CN, —NR₁₁C(O)R₁₁,—S(O)₂NR₁₁R₁₁, —NR₁₁S(O)₂R₁₁, —NO₂, alkyl substituted with 1-4substituent(s) independently selected from F, Cl, Br, I, or R₁₃,cycloalkyl substituted with 1-4 substituent(s) independently selectedfrom F, Cl, Br, I, or R₁₃, or heterocycloalkyl substituted with 1-4substituent(s) independently selected from F, Cl, Br, I, or R₁₃; R₁₉isH, alkyl, cycloalkyl, substituted alkyl, halogenated alkyl, substitutedphenyl, or substituted naphthyl; or pharmaceutically acceptable salt,racemic mixture, and pure enantiomer thereof.
 2. The compound of claim1, wherein X is O.
 3. The compound of claim 2, wherein R, is H, alkyl,or cycloalkyl.
 4. The compound of claim 3, wherein W is (a).
 5. Thecompound of claim 4, wherein (a) is thieno[2,3-b]pyridin-2-yl,thieno[2,3-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl,thieno[3,2-b]pyridin-2-yl, thieno[3,2-b]pyridin-5-yl,thieno[3,2-b]pyridin-6-yl, thieno[2,3-c]pyridin-2-yl,thieno[2,3-c]pyridin-5-yl, thieno[3,2-c]pyridin-2-yl,thieno[3,2-c]pyridin-6-yl, furo[3,2-c]pyridin-2-yl,furo[3,2-c]pyridin-6-yl, furo[2,3-b]pyridin-2-yl,furo[2,3-c]pyridin-2-yl, furo[2,3-c]pyridin-5-yl,2,3-dihydrofuro[2,3-c]pyridin-5-yl, or 1H-pyrrolo[2,3-c]pyridin-5-yl,optionally substituted on up to 4 different carbon atoms as valencyallows and as allowed by the definition of W with F, Br, Cl, I, —CN,—NO₂, —CF₃, —OR₅, —OR₁₉, —SR₅, —SR₁₉, —N(R₅)₂, —N(R₁₀)₂, —C(O)R₁₉,—CO₂R₁₉, —C(O)N(R₁₀)₂, —S(O)₂R₁₉, alkyl, substituted alkyl, halogenatedalkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl,substituted alkynyl, halogenated alkynyl, aryl, R₇, R₉, and furtheroptionally substituted on a nitrogen as allowed by the definition of Wwith alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇, or R₉,provided that one carbon is used to bond W to the core molecule.
 6. Thecompound of claim 5, wherein the optional substituents are selected fromF, Br, Cl, I, —CN, —CF₃, —OR₅, —SR₅, —N(R₅)₂, —C(O)R₅, —CO₂R₅,—C(O)N(R₁₀)₂, —S(O)₂R₅, lower alkyl, lower substituted alkyl, or loweralkynyl, where R₁₀ is H, lower halogenated alkyl, or lower alkyloptionally substituted with —CN, —CF₃, —NO₂, —OR₁₁, —SR₁₁, —NR₁₁R₁₁,—C(O)R₁₁, —C(O)NR₁₁R₁₁, —NR₁₁C(O)R₁₁, —S(O)₂NR₁₁R₁₁, or —NR₁₁S(O)₂R₁₁,wherein R₁₁ is H, lower alkyl, lower halogenated alkyl, or lowersubstituted alkyl. 7-13. (canceled)
 14. The compound of claim 6, whereinAzabicyclo is I , III, or IV.
 15. The compound of claim 14, whereinAzabicyclo is I and wherein R₂ is alkyl, halogenated alkyl, orsubstituted alkyl, or wherein Azabicyclo is III or IV and wherein R₂₋₃is H, alkyl, or substituted alkyl.
 16. The compound of claim 15, whereinthe compound is N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl )-azabicyclo[2.2.2]oct-3-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-7-chlorofuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-furo[2,3-b]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-furo[2,3-b]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-furo[2,3-b]pyridine-2-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-7-(methylsulfanyl)furo[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-2-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-6-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-c]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-c]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-c]pyridine-2-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-2-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-6-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-c]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-c]pyridine-2-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-2-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-6-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromofuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl )-azabicyclo[2.2.2]oct-3-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chlorofuro[2,3-c]pyridine-5-carboxamide;or a pharmaceutically acceptable salt thereof, wherein the compound isthe pure enantiomer or a racemic mixture thereof.
 17. The compound ofclaim 16, wherein the compound is N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methylfuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methylfuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethylfuro[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-b]pyridine-6-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-b]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-b]pyridine-6-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[2,3-c]pyridine-5-carboxamide;N-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-thieno[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-thieno[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-thieno[3,2-c]pyridine-6-carboxamide; ora pharmaceutically acceptable salt thereof, wherein the compound is thepure enantiomer or a racemic mixture thereof.
 18. The compound accordingto claim 15, wherein the compound isN-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-cyanofuro[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-fluorofuro[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-chlorofuro[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-bromofuro[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-iodofuro[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;2-(acetylamino)-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-(pyrrolidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-2-[dimethylamino]furo[3,2-c]pyridine-6-carboxamide;N-6-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-2,6-dicarboxamide;2-acetyl-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-6-carboxamide; methyl6-{[1-(6-methyl)-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}furo[3,2-c]pyridine-2-carboxylate;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-vinylfuro[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-cyanofuro[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-fluorofuro[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-iodofuro[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;3-(acetylamino)-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;N-5-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-3,5-dicarboxamide;N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]-3-formylfuro[2,3-c]pyridine-5-carboxamide;3-acetyl-N-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;methyl5-{[1-(6-methyl)-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}furo[2,3-c]pyridine-3-carboxylate;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyanofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-fluorofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-chlorofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-bromofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-iodofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;2-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-(pyrrolidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-[dimethylamino]furo[3,2-c]pyridine-6-carboxamide;N-6-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-2,6-dicarboxamide;2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[3,2-c]pyridine-6-carboxamide;methyl6-[(2-azabicyclo[2.2.1]hept-5-ylamino)carbonyl]furo[3,2-c]pyridine-2-carboxylate;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-vinylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyanofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-fluorofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-iodofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;3-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;N-5-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-3,5-dicarboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-formylfuro[2,3-c]pyridine-5-carboxamide;3-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)furo[2,3-c]pyridine-5-carboxamide;methyl5-[(2-azabicyclo[2.2.1]hept-5-ylamino)carbonyl]furo[2,3-c]pyridine-3-carboxylate;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-ethynylfuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-prop-1-ynylfuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyanofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-fluorofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-chlorofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-bromofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-iodofuro[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-trifluoromethylfuro[3,2-c]pyridine-6-carboxamide;2-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-(pyrrolidin-1-yl)furo[3,2-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-[dimethylamino]furo[3,2-c]pyridine-6-carboxamide;N-6-[l-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-2,6-dicarboxamide;2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[3,2-c]pyridine-6-carboxamide;methyl6-[2-azabicyclo[2.2.1]hept-6-ylamino)carbonyl]furo[3,2-c]pyridine-2-carboxylate;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-vinylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynylfuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyanofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-fluorofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-iodofuro[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-trifluoromethylfuro[2,3-c]pyridine-5-carboxamide;3-(acetylamino)-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-(pyrrolidin-1-yl)furo[2,3-c]pyridine-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-[dimethylamino]furo[2,3-c]pyridine-5-carboxamide;N-5-[1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-3,5-dicarboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-formylfuro[2,3-c]pyridine-5-carboxamide;3-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)furo[2,3-c]pyridine-5-carboxamide;methyl5-[2-azabicyclo[2.2.1]hept-6-ylamino)carbonyl]furo[2,3-c]pyridine-3-carboxylate;or a pharmaceutically acceptable salt thereof, wherein the compound isthe pure enantiomer or a racemic mixture thereof.
 19. The compound ofclaim 3, wherein W is (b).
 20. The compound of claim 19, wherein (b) isthieno[3,4-c]pyridin-6-yl, optionally substituted on up to 4 differentcarbon atoms as valency allows and as allowed by the definition of Wwith F, Br, Cl, I, —CN, —NO₂, —CF₃, —OR₅, —OR₁₉, —SR₅, —SR₁₉, —N(R₅)₂,—N(R₁₀)₂, —C(O)R₁₉, —CO₂R₁₉, —C(O)N(R₁₀)₂, —S(O)₂R₁₉, alkyl, substitutedalkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenatedalkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, aryl, R₇,R₉, and further optionally substituted on a nitrogen as allowed by thedefinition of W with alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, R₇, or R₉, provided that one carbon is used to bond Wto the core molecule. 21-25. (canceled)
 26. The compound of claim 20,wherein Azabicyclo is I, III, or IV.
 27. The compound of claim 26,wherein Azabicyclo is I and wherein R₂ is alkyl, halogenated alkyl, orsubstituted alkyl, or wherein Azabicyclo is III or IV and wherein R₂₋₃is H, alkyl, or substituted alkyl.
 28. The compound of claim 27, whereinthe compound isN-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)thieno[3,4-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)thieno[3,4-c]pyridine-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)thieno[3,4-c]pyridine-6-carboxamide; ora pharmaceutically acceptable salt thereof, wherein the compound is thepure enantiomer or a racemic mixture thereof.
 29. The compound of claim3, wherein W is (c).
 30. The compound of claim 29, wherein (c) isbenzothieno[3,2-c]pyridine-3-yl, benzothieno[2,3-c]pyridin-3-yl,benzofuro[3,2-c]pyridin-3-yl, or benzofuro[2,3-c]pyridin-3-yl,optionally substituted on up to 4 different carbon atoms as valencyallows and as allowed by the definition of W with F, Br, Cl, I, —CN,—NO₂, —CF₃, —OR₅, —OR₁₉, —SR₅, —SR₁₉, —N(R₅)₂, —N(R₁₀)₂, —C(O)R₁₉,—CO₂R₁₉, —C(O)N(R₁₀)₂, —S(O)₂R₁₉, alkyl, substituted alkyl, halogenatedalkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl,substituted alkynyl, halogenated alkynyl, aryl, R₇, R₉, and furtheroptionally substituted on a nitrogen as allowed by the definition of Wwith alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocycloalkyl, substituted heterocycloalkyl, R₇, or R₉,provided that one carbon is used to bond W to the core molecule. 31-35.(canceled)
 36. The compound of claim 30, wherein Azabicyclo is I, III,or IV.
 37. The compound of claim 36, wherein Azabicyclo is I and whereinR₂ is alkyl, halogenated alkyl, or substituted alkyl, or whereinAzabicyclo is III or IV, and wherein R₂₋₃ is H, alkyl, or substitutedalkyl.
 38. The compound of claim 37, wherein the compound isN-(1-(6-methyl)-azabicyclo[2.2.2]oct-3-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-benzothieno[3,2-c]pyridine-3-carboxamide;or a pharmaceutically acceptable salt thereof, wherein the compound isthe pure enantiomer or a racemic mixture thereof.
 39. A pharmaceuticalcomposition comprising a compound according to claim 1, ananti-psychotic agent, and a pharmaceutically acceptable excipient. 40.The pharmaceutical composition according to claim 39, wherein saidcompound and said agent are to be independently administered rectally,topically, orally, sublingually, or parenterally for a therapeuticallyeffective interval.
 41. The pharmaceutical composition according toclaim 39, wherein said compound is administered in an amount of fromabout 0.001 to about 100 mg/kg of body weight of said mammal per day.42. The pharmaceutical composition according to claim 39, wherein saidcompound is administered in an amount of from about 0.1 to about 50mg/kg of body weight of said mammal per day.
 43. The pharmaceuticalcomposition according to claim 39, comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 44. Thepharmaceutical composition according to claim 43, wherein said compoundis administered rectally, topically, orally, sublingually, orparenterally for a therapeutically effective interval.
 45. Thepharmaceutical composition according to claim 43, wherein said compoundis administered in an amount of from about 0.001 to about 100 mg/kg ofbody weight of said mammal per day.
 46. The pharmaceutical compositionaccording to claim 43, wherein said compound is administered in anamount of from about 0.1 to about 50 mg/kg of body weight of said mammalper day.
 47. A method for treating a disease or condition in a mammal inneed thereof, wherein the mammal would receive symptomatic relief fromthe administration of an α7 nicotinic acetylcholine receptor agonistcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim
 1. 48. The method according toclaim 47, wherein the disease or condition is cognitive and attentiondeficit symptoms of Alzheimer's, neurodegeneration associated withdiseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), or senile dementia.
 49. The method according toclaim 47, wherein the disease or condition is schizophrenia orpsychosis.
 50. The method of claim 49, wherein the mammal would receivesymptomatic relief from the administration of a therapeuticallyeffective amount of α7 nicotinic acetylcholine receptor agonist and ananti-psychotic agent for a therapeutically effective interval.
 51. Themethod according to claim 47, wherein the disease or condition isdepression, or anxiety and general anxiety disorders and post traumaticstress disorder.
 52. The method according to claim 47, wherein thedisease or condition is attention deficit disorder, or attention deficithyperactivity disorder.
 53. The method according to claim 47, whereinthe disease or condition is mood and affective disorders, amyotrophiclateral sclerosis, borderline personality disorder, traumatic braininjury, behavioral and cognitive problems in general and associated withbrain tumors, AIDS dementia complex, dementia associated with Down'ssyndrome, dementia associated with Lewy Bodies, Huntington's disease,Parkinson's disease, tardive dyskinesia, Pick's disease, dysregulationof food intake including bulemia and anorexia nervosa, withdrawalsymptoms associated with smoking cessation and dependant drug cessation,Gilles de la Tourette's Syndrome, age-related macular degeneration,glaucoma, neurodegeneration associated with glaucoma, or symptomsassociated with pain.